This variant in exon 6 of the G6PD gene results in the amino acid substitution from Serine to Phenylalanine at codon 188 (p.Ser188Phe) with the sequence change of c.653C>T (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. This variant is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This variant has previously been reported for Anemia, Nonspherocytic Hemolytic, Due to G6pd Deficiency by T J Vulliamy et al., 1988. The Missense Variants Z-Score for this variant is 2.60. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. This variant has been reported six individuals in homozygous condition, in 109 individuals in hemizygous condition and 25 individuals in heterozygous conditions. (Hellani et al. 2009; PMID: 19594365), (Moiz et al. 2012; PMID: 22906047), (Santana et al. 2013; PMID: 23479361), (Molou et al. 2014; PMID: 24460025) and (Jamornthanyawat et al. 2014; PMID: 24586352).
ClinVar Genomic variation as it relates to human health
NM_000402.4(G6PD):c.653C>T (p.Ser218Phe)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(54)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
54
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of 4 Haplotypes
- Identifiers
-
NM_000402.4(G6PD):c.653C>T (p.Ser218Phe)
Variation ID: 100057 Accession: VCV000100057.102
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq28 X: 154534419 (GRCh38) [ NCBI UCSC ] X: 153762634 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 5, 2015 Nov 17, 2024 Oct 28, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001360016.2:c.563C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001346945.1:p.Ser188Phe missense NM_000402.4:c.653C>T NP_000393.4:p.Ser218Phe missense NM_001042351.2:c.[563C>T] NM_001042351.3:c.563C>T NP_001035810.1:p.Ser188Phe missense NC_000023.11:g.154534419G>A NC_000023.10:g.153762634G>A NG_009015.2:g.18154C>T - Protein change
- S188F, S218F
- Other names
-
G6PD, SER188PHE
G6PD Birmingham
G6PD Cagliari
G6PD Dallas
G6PD Mediterranean
G6PD Panama
G6PD Sassari
- Canonical SPDI
- NC_000023.11:154534418:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00079 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00028
Trans-Omics for Precision Medicine (TOPMed) 0.00056
1000 Genomes Project 0.00079
1000 Genomes Project 30x 0.00083
The Genome Aggregation Database (gnomAD), exomes 0.00255
Exome Aggregation Consortium (ExAC) 0.00265
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| G6PD | - | - |
GRCh38 GRCh37 |
656 | 976 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (13) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000079409.64 | |
|
G6PD MEDITERRANEAN
|
other (1) |
no assertion criteria provided
|
May 11, 2018 | RCV000011086.13 |
|
G6PD CAGLIARI
|
other (1) |
no assertion criteria provided
|
May 11, 2018 | RCV000011088.13 |
|
G6PD SASSARI
|
other (1) |
no assertion criteria provided
|
May 11, 2018 | RCV000011087.13 |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 5, 2023 | RCV000445579.15 | |
| Pathogenic/Likely pathogenic (26) |
criteria provided, multiple submitters, no conflicts
|
Oct 28, 2024 | RCV000179363.64 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000477810.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 14, 2016 | RCV000623137.11 | |
|
G6PD deficient hemolytic anemia
|
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001250219.9 |
|
Hemolytic anemia, G6PD deficient (favism)
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 14, 2020 | RCV001265539.9 |
| Pathogenic (2) |
criteria provided, single submitter
|
Mar 28, 2024 | RCV001528124.12 | |
|
G6PD-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
May 30, 2024 | RCV003925095.2 |
|
See cases
|
Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 28, 2023 | RCV004584350.1 |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Aug 13, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
(X-linked inheritance)
Affected status: yes
Allele origin:
unknown,
germline
|
UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255508.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Observation 1:
Number of individuals with the variant: 1
Age: 30-39 years
Sex: male
Ethnicity/Population group: European Caucasian
Observation 2:
Number of individuals with the variant: 1
Age: 10-19 years
Sex: male
Ethnicity/Population group: Armenian
|
|
|
Pathogenic
(Jun 06, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677998.1
First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
|
|
|
Pathogenic
(Jan 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150112.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV001430927.1
First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020 |
Comment:
This variant in exon 6 of the G6PD gene results in the amino acid substitution from Serine to Phenylalanine at codon 188 (p.Ser188Phe) with the … (more)
This variant in exon 6 of the G6PD gene results in the amino acid substitution from Serine to Phenylalanine at codon 188 (p.Ser188Phe) with the sequence change of c.653C>T (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. This variant is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This variant has previously been reported for Anemia, Nonspherocytic Hemolytic, Due to G6pd Deficiency by T J Vulliamy et al., 1988. The Missense Variants Z-Score for this variant is 2.60. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. This variant has been reported six individuals in homozygous condition, in 109 individuals in hemizygous condition and 25 individuals in heterozygous conditions. (Hellani et al. 2009; PMID: 19594365), (Moiz et al. 2012; PMID: 22906047), (Santana et al. 2013; PMID: 23479361), (Molou et al. 2014; PMID: 24460025) and (Jamornthanyawat et al. 2014; PMID: 24586352). (less)
Clinical Features:
X-linked recessive inheritance (present)
Indication for testing: Decreased level of G6PD enzyme (<2.4 U/dL)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Asian
Geographic origin: India
Comment on evidence:
This variant in exon 6 of the G6PD gene results in the amino acid substitution from Serine to Phenylalanine at codon 188 (p.Ser188Phe) with the … (more)
This variant in exon 6 of the G6PD gene results in the amino acid substitution from Serine to Phenylalanine at codon 188 (p.Ser188Phe) with the sequence change of c.653C>T (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. (less)
Method: Sanger sequencing-based DNA analysis was used to identify the variants
Testing laboratory: Org:507720
Testing laboratory interpretation: Pathogenic
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447745.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Abnormal circulating glucose-6-phosphate dehydrogenase concentration (present)
Sex: female
|
|
|
Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: yes
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001810223.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
|
Likely pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572646.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. However, this variant is the … (more)
The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. However, this variant is the most common cause of G6PD deficiency in the Mediterranean area, the Middle East and the India subcontinent (ClinVar ID: VCV000100057). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22906047 , 24460025 , 3393536). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.49). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebellar ataxia (present)
|
|
|
Pathogenic
(May 08, 2023)
|
criteria provided, single submitter
Method: research
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: yes
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV003924319.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
|
|
|
Pathogenic
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023784.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Aug 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: unknown
Allele origin:
inherited
|
New York Genome Center
Accession: SCV004176061.2
First in ClinVar: Dec 17, 2023 Last updated: Mar 16, 2024 |
Clinical Features:
Intellectual disability (present) , Delayed speech and language development (present) , Developmental regression (present) , Autistic behavior (present) , Tics (present) , Jaundice (present) , … (more)
Intellectual disability (present) , Delayed speech and language development (present) , Developmental regression (present) , Autistic behavior (present) , Tics (present) , Jaundice (present) , Constipation (present) (less)
Secondary finding: no
|
|
|
Likely pathogenic
(Apr 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV005038977.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Comment:
A heterozygous variant in exon 6 of the G6PD gene that results in the amino acid substitution of Phenylalanine for Serine at codon 188 was … (more)
A heterozygous variant in exon 6 of the G6PD gene that results in the amino acid substitution of Phenylalanine for Serine at codon 188 was detected. The observed variant c.563C>T (p.Ser188Phe) was previously been reported in the 1000 genomes, gnomAD and TOPMed databases with MAF of 0.0833%, 0.1479% and 0.0559% respectively. The in silico prediction of the variant is damaging by SIFT, FATHMM and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. (less)
Age: 20-29 years
Sex: female
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
|
|
Pathogenic
(Dec 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001523186.3
First in ClinVar: Mar 22, 2021 Last updated: Jun 09, 2024 |
|
|
|
Pathogenic
(Mar 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Malaria, susceptibility to
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004195378.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(May 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000231598.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 45
Sex: mixed
|
|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001142109.1
First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020 |
|
|
|
Pathogenic
(Apr 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hemolytic anemia, G6PD deficient (favism)
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001443686.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
This variant is also known as c.563C>T, p.Ser188Phe (using the alternative transcripts NM_001042351.3 and NM_001360016.2).This alteration has been previously reported as hemizygous change in patients … (more)
This variant is also known as c.563C>T, p.Ser188Phe (using the alternative transcripts NM_001042351.3 and NM_001360016.2).This alteration has been previously reported as hemizygous change in patients with hemolytic anemia associated with Glucose 6-phosphate deficiency (PMID: 28067620, 24586352, 11445808, 12768444). Functional studies demonstrate decreased enzyme activity in the circulating erythrocytes of individuals with this variant, increased affinity for G6P and decreased in vitro thermostability (PMID: 9342374, 3393536). It is present in the gnomAD population database at a frequency of 0.23% with 471/204697 in heterozygous state, 6/204697 in homozygous state and 256/204697 in hemizygous state. In silico analyses support a deleterious effect of the c.653C>T (p.Ser218Phe) variant on protein function. Based on the available evidence, the c.653C>T (p.Ser218Phe) variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581618.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4, PP3, PP4
|
Number of individuals with the variant: 4
Sex: male
|
|
|
Pathogenic
(Aug 12, 2022)
|
criteria provided, single submitter
Method: curation
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: yes
Allele origin:
maternal
|
Dunham Lab, University of Washington
Accession: SCV002599337.1
First in ClinVar: Nov 13, 2022 Last updated: Nov 13, 2022 |
Comment:
Variant found in unrelated hemizygotes with deficiency, many with anemia, jaundice, and favism, and some with CNSHA (PS4_M, PP4). Phenotype transmitted with variant from mother … (more)
Variant found in unrelated hemizygotes with deficiency, many with anemia, jaundice, and favism, and some with CNSHA (PS4_M, PP4). Phenotype transmitted with variant from mother to son (PP1). Decreased activity in red blood cells (0-33%) (PS3). Predicted to be deleterious by REVEL and SIFT (PP3). Reported as pathogenic by multiple clinical testing groups (PP5). Not found in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1516, Prior_P 0.1). (less)
|
|
|
Pathogenic
(May 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321681.10
First in ClinVar: Mar 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate decreased enzyme activity in circulating erythrocytes, increased affinity for G6P, and decreased in vitro thermostability (Vulliamy et al., 1998); In silico … (more)
Published functional studies demonstrate decreased enzyme activity in circulating erythrocytes, increased affinity for G6P, and decreased in vitro thermostability (Vulliamy et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23479361, 27535533, 31152693, 33413378, 31322791, 24460025, 3393536, 27884173, 19594365, 24586352, 1978555, 25548459, 28492530, 8611726, 28492532, 27853304, 27108201, 30097005, 31863082, 33069889, 31019026, 31980526, 34272389, 34426522, 33072997, 33083013, 30755392, 12215013, 32535712, 32860008, 33726816, 1978554, 22906047) (less)
|
|
|
Pathogenic
(May 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV004013915.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PS3, PS4, PM1, PP5
|
|
|
Pathogenic
(Oct 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
G6PD deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122524.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: G6PD c.653C>T (p.Ser218Phe) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal domain (IPR022675) of the encoded protein sequence. … (more)
Variant summary: G6PD c.653C>T (p.Ser218Phe) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal domain (IPR022675) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 183257 control chromosomes in the gnomAD database, including 6 homozygotes. This variant has a high frequency in South Asian population (0.017) in gnomAD. c.653C>T (Also known as G6PD Mediterranean) is a common cause of G6PD deficiency in the Mediterranean area, the Middle East and the India subcontinent (Kurdi-Haidar_1990). c.653C>T has been reported in the literature in multiple individuals affected with severe Glucose 6 Phosphate Dehydrogenase Deficiency (Kurdi-Haidar_1990), neonatal hyperbilirubinaemia (Moiz_2012) and hemolytic anemia (examples: Vulliamy_1988, Similuk_2022, and Naofal_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Vulliamy_1988). The following publications have been ascertained in the context of this evaluation (PMID: 36703223, 35753512, 22906047, 3393536, 1978555). Thirty submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Nov 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885494.9
First in ClinVar: Feb 15, 2018 Last updated: Feb 20, 2024 |
Comment:
The G6PD c.563C>T; p.Ser188Phe variant (rs5030868), also known as G6PD Mediterranean, is reported in the literature in multiple individuals affected with hemolytic anemia, hyperbilirubinemia and … (more)
The G6PD c.563C>T; p.Ser188Phe variant (rs5030868), also known as G6PD Mediterranean, is reported in the literature in multiple individuals affected with hemolytic anemia, hyperbilirubinemia and G6PD deficiency (Hellani 2009, Jamornthanyawat 2014, Kaplan 1997, Moiz 2012, Molou 2014, Vulliamy 1988). Functional analyses of the variant protein shows decreased enzyme activity, increased affinity for G6P and decreased in vitro thermostability (Moiz 2012, Molou 2014, Vulliamy 1988). This variant is reported in ClinVar (Variation ID: 100057). This variant is found predominantly in the South Asian population with an allele frequency of 1.7% (331/19,078 alleles, including 4 homozygotes and 211 hemizygotes) in the Genome Aggregation Database. The serine at codon 188 is moderately conserved, but computational analyses predict that this variant is deleterious (REVEL: 0.811). Based on available information, this variant is considered to be pathogenic. References: Hellani A et al. G6PD Mediterranean S188F codon mutation is common among Saudi sickle cell patients and increases the risk of stroke. Genet Test Mol Biomarkers. 2009 Aug;13(4):449-52. Jamornthanyawat N et al. A population survey of the glucose-6-phosphate dehydrogenase (G6PD) 563C>T (Mediterranean) mutation in Afghanistan. PLoS One. 2014 Feb 21;9(2):e88605. Kaplan M et al. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12128-32. Moiz B et al. Neonatal hyperbilirubinemia in infants with G6PD c.563C > T Variant. BMC Pediatr. 2012 Aug 20;12:126. Molou E et al. Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency in Greek newborns: the Mediterranean C563T mutation screening. Scand J Clin Lab Invest. 2014 Apr;74(3):259-63. Vulliamy TJ et al. Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5171-5. (less)
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Pathogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004024683.3
First in ClinVar: Aug 19, 2023 Last updated: Aug 04, 2024 |
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Pathogenic
(May 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073219.2
First in ClinVar: Feb 05, 2022 Last updated: Oct 08, 2024 |
Comment:
The missense variant c.563C>T(p.Ser188Phe) in G6PD gene has been observed in individual(s) with G6PD deficiency (Thedsawad A, et. al., 2022;Arunachalam AK, et. al., 2020; AlJaouni … (more)
The missense variant c.563C>T(p.Ser188Phe) in G6PD gene has been observed in individual(s) with G6PD deficiency (Thedsawad A, et. al., 2022;Arunachalam AK, et. al., 2020; AlJaouni et.al., 2011; Jamornthanyawat et. al., 2014). Experimental studies have shown that this missense change affects G6PD function (Molouet. al., 2014). It is commonly reported in individuals of Mediterranean, Middle Eastern, or Indian ancestry (AlJaouni et. al., 2011;Jamornthanyawat et. al., 2014). The observed variant has been reported with allele frequency of 0.2 % in gnomAD database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). Computational evidence (Polyphen -Benign , SIFT - damaging and MutationTaster -disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Ser188Phe in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 188 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of blood and blood-forming tissues (present)
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Pathogenic
(Jul 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: unknown
Allele origin:
maternal
|
Institute of Immunology and Genetics Kaiserslautern
Accession: SCV005382225.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Comment:
ACMG Criteria: PS3, PS4, PP3, PP5; Variant was found in hemizygous state.
Clinical Features:
Myopathy (present) , Failure to thrive (present)
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Pathogenic
(Oct 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001441024.4
First in ClinVar: Oct 31, 2020 Last updated: Nov 17, 2024 |
Clinical Features:
Spontaneous hemolytic crises (present)
Sex: male
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Pathogenic
(Feb 14, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Hemolytic anemia due to G6PD deficiency
Affected status: unknown
Allele origin:
germline
|
Courtagen Diagnostics Laboratory, Courtagen Life Sciences
Accession: SCV000236525.2
First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Malaria, susceptibility to
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893824.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
G6PD deficient hemolytic anemia
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001424421.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001426527.1
First in ClinVar: Aug 10, 2020 Last updated: Aug 10, 2020 |
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Pathogenic
(Dec 14, 2016)
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criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741900.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Chronic fatigue (present) , Myalgia (present) , Pectus excavatum (present) , Orthopnea (present) , Insomnia (present) , Chest pain (present) , Aortic root dilatation (present) … (more)
Chronic fatigue (present) , Myalgia (present) , Pectus excavatum (present) , Orthopnea (present) , Insomnia (present) , Chest pain (present) , Aortic root dilatation (present) , Abnormal levels of creatine kinase in blood (present) , Paresthesia (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Intellectual disability (present) , Generalized hypotonia (present) , Seizures (present) , Postnatal microcephaly (present) , Cortical visual impairment (present) , Inappropriate laughter (present) , Micropenis … (more)
Intellectual disability (present) , Generalized hypotonia (present) , Seizures (present) , Postnatal microcephaly (present) , Cortical visual impairment (present) , Inappropriate laughter (present) , Micropenis (present) , Hypospadias, penile (present) , Constipation (present) , Gastroesophageal reflux (present) , Esophagitis (present) , Failure to thrive (present) , Triangular face (present) , Low-set ears (present) , Partial agenesis of the corpus callosum (present) (less)
Sex: male
Ethnicity/Population group: Ashkenazi Jewish/Czech/Italian/Sephardic Jewish/Spanish/Polish/Russian
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Pathogenic
(Dec 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818285.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
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Pathogenic
(Jan 18, 2023)
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criteria provided, single submitter
Method: clinical testing
|
G6PD deficiency
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV000915299.2
First in ClinVar: May 27, 2019 Last updated: Jul 22, 2023 |
Comment:
The G6PD c.563C>T (p.Ser188Phe) missense variant, also referred to as G6PD Mediterranean, results in the substitution of serine at amino acid position 188 with phenylalanine. … (more)
The G6PD c.563C>T (p.Ser188Phe) missense variant, also referred to as G6PD Mediterranean, results in the substitution of serine at amino acid position 188 with phenylalanine. Across a selection of the available literature, the variant has been identified in a homozygous state in six probands, in a hemizygous state in 109 probands and in a heterozygous state in 25 probands (PMID: 19594365; 22906047; 23479361; 24460025; 24586352). The c.563C>T variant was reported in seven of 42 controls in a presumed heterozygous state and is reported at a frequency of 0.017450 in the South Asian population of the Genome Aggregation Database. The c.563C>T variant resulted in 0-7% residual enzyme activity in red blood cells compared to wild type and caused decreased thermostability and reduced catalytic activity (PMID: 3393536). Based on the collective evidence, the c.563C>T (p.Ser188Phe) variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency. (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
(X-linked inheritance)
Affected status: yes
Allele origin:
maternal
|
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center
Accession: SCV003929453.1
First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023 |
Indication for testing: Neonatal hyperbilirubinemia
Age: 0-9 years
Sex: male
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Pathogenic
(Jun 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225543.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Number of individuals with the variant: 9
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Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000647802.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 188 of the G6PD protein (p.Ser188Phe). … (more)
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 188 of the G6PD protein (p.Ser188Phe). This variant is present in population databases (rs5030868, gnomAD 1.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with G6PD deficiency (PMID: 1978554, 8611726, 15315792, 16119988, 22018328, 24586352). It is commonly reported in individuals of Mediterranean, Middle Eastern, or Indian ancestry (PMID: 1978554, 8611726, 15315792, 16119988, 22018328, 24586352). ClinVar contains an entry for this variant (Variation ID: 100057). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PD protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PD function (PMID: 3393536, 22906047, 24460025). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV002506445.2
First in ClinVar: May 07, 2022 Last updated: Jul 07, 2024 |
Comment:
ACMG categories: PS3,PM1,PP3,PP5,BP1
Number of individuals with the variant: 1
Clinical Features:
Decreased glucose-6-phosphate dehydrogenase level in blood (present)
Age: 0-9 years
Sex: male
Tissue: blood
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Pathogenic
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
(X-linked recessive inheritance)
Affected status: no
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV003921882.2
First in ClinVar: May 06, 2023 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with G6PD deficient haemolytic anaemia (favism) (MIM#300908). (I) 0109 - This gene is associated with X-linked recessive disease. Hemizygous males and homozygous females are commonly affected; however, some heterozygous female carriers can also be affected depending on X-inactivation. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (203 heterozygotes, 6 homozygotes, 256 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glucose-6-phosphate dehydrogenase NAD binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is reported as one of the most common severe pathogenic variants in this gene (ClinVar, LOVD, PMID: 27853304). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The variant has been shown to result in highly impaired enzyme activity (PMID: 3393536, PMID: 7211845). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Nov 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197994.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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|
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Pathogenic
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001150542.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Comment:
G6PD: PP1:Strong, PS4, PS3:Moderate
Number of individuals with the variant: 144
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|
Pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: research
|
Malaria, susceptibility to
Anemia, nonspherocytic hemolytic, due to G6PD deficiency Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: unknown
Allele origin:
paternal
|
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536869.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
|
|
|
other
(May 11, 2018)
|
no assertion criteria provided
Method: literature only
|
G6PD SASSARI
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000031314.7
First in ClinVar: Apr 04, 2013 Last updated: May 14, 2018 |
Comment on evidence:
See Kirkman et al. (1964), Ben-Bassat and Ben-Ishay (1969), Lenzerini et al. (1969), Testa et al. (1980), and Morelli et al. (1984). A change from … (more)
See Kirkman et al. (1964), Ben-Bassat and Ben-Ishay (1969), Lenzerini et al. (1969), Testa et al. (1980), and Morelli et al. (1984). A change from cytosine to thymine at base position 563 (in exon 6) causes a change from serine to phenylalanine in amino acid position 188 (Vulliamy et al., 1988). De Vita et al. (1989) found that G6PD Mediterranean, G6PD Sassari, and G6PD Cagliari have the same mutational change, resulting from a TCC-to-TTC mutation in exon 6. There is a second silent mutation of TAC-to-TAT at codon 437 in exon 11 (C-to-T at nucleotide 1311; see 305900.0018); both codons code for tyrosine. This mutation is a polymorphism, causes class 2 abnormality, and creates a new MboII site. Beutler and Kuhl (1990) studied the distribution of the nucleotide polymorphism C1311T in diverse populations. Only 1 of 22 male subjects from Mediterranean countries who had the G6PD Mediterranean-563T genotype had a C at nucleotide 1311, which is the more frequent finding in this group. In contrast, both G6PD Mediterranean-563T males from the Indian subcontinent had the usual C at nucleotide 1311. Beutler and Kuhl (1990) interpreted these findings as suggesting that the same mutation at nucleotide 563 arose independently in Europe and in Asia. Similar studies were done by Kurdi-Haidar et al. (1990) in 21 unrelated individuals with G6PD Mediterranean from Saudi Arabia, Iraq, Iran, Jordan, Lebanon, and Israel. All but 1 had the 563 mutation, and, of these, all but 1 had the C-to-T change at nucleotide 1311. Among another 24 unrelated Middle Eastern persons with normal G6PD activity, 4 had the silent mutation at position 1311 in the absence of the deficiency mutation at position 563. Kurdi-Haidar et al. (1990) concluded that most Middle Eastern subjects with the G6PD Mediterranean phenotype have the same mutation as that found in Italy; that the silent mutation is an independent polymorphism in the Middle East, with a frequency of about 0.13; and that the mutation leading to G6PD Mediterranean deficiency probably arose on a chromosome that already carried the silent mutation. In Nepal, Matsuoka et al. (2003) tested 300 males for G6PD deficiency and identified 2 (0.67%) who were G6PD deficient. Compared with normal controls, G6PD activity was 12% and 26%, respectively. Both subjects had the 563C-T substitution of G6PD Mediterranean (ser188 to phe), and both had the silent 1311C-T change. A similar second change has been described in persons living in Mediterranean countries and Middle East countries. However, the form of G6PD Mediterranean found in India and Pakistan has no replacement at nucleotide 1311. Thus, the 2 subjects in Kathmandu, Nepal, would be closer to people in Middle East countries than people in India. Corcoran et al. (1992) described a G6PD mutant biochemically indistinguishable from the common variety due to a C-to-T mutation at nucleotide 563. Instead, a C-to-T transition was found at nucleotide 592 in exon 6, changing an arginine residue to a cysteine residue only 10 amino acids downstream from the Mediterranean mutation. The new variant was named G6PD Coimbra (305900.0031). Kaplan et al. (1997) presented data suggesting that the coexistence of Mediterranean type G6PD deficiency with the TA insertion polymorphism of the promoter of the UGT1A1 gene (191740.0011), which is associated with Gilbert syndrome (143500) in adults, is responsible for the development of neonatal hyperbilirubinemia. This is the most devastating clinical consequence of G6PD deficiency; it can be severe and result in kernicterus or even death. Kaplan et al. (1997) found that neither G6PD deficiency nor the polymorphism of UDP glucuronosyltransferase alone increased the incidence of neonatal hyperbilirubinemia, but in combination they did. The authors suggested that this gene interaction may serve as a paradigm of the interaction of benign genetic polymorphisms in the causation of disease. Kaplan et al. (2001) reported 2 premature female neonates heterozygous for the G6PD Mediterranean mutation who presented with severe hyperbilirubinemia requiring exchange transfusions. Both had had normal G6PD biochemical screening tests. (less)
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|
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other
(May 11, 2018)
|
no assertion criteria provided
Method: literature only
|
G6PD CAGLIARI
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000031315.7
First in ClinVar: Apr 04, 2013 Last updated: May 14, 2018 |
Comment on evidence:
See Kirkman et al. (1964), Ben-Bassat and Ben-Ishay (1969), Lenzerini et al. (1969), Testa et al. (1980), and Morelli et al. (1984). A change from … (more)
See Kirkman et al. (1964), Ben-Bassat and Ben-Ishay (1969), Lenzerini et al. (1969), Testa et al. (1980), and Morelli et al. (1984). A change from cytosine to thymine at base position 563 (in exon 6) causes a change from serine to phenylalanine in amino acid position 188 (Vulliamy et al., 1988). De Vita et al. (1989) found that G6PD Mediterranean, G6PD Sassari, and G6PD Cagliari have the same mutational change, resulting from a TCC-to-TTC mutation in exon 6. There is a second silent mutation of TAC-to-TAT at codon 437 in exon 11 (C-to-T at nucleotide 1311; see 305900.0018); both codons code for tyrosine. This mutation is a polymorphism, causes class 2 abnormality, and creates a new MboII site. Beutler and Kuhl (1990) studied the distribution of the nucleotide polymorphism C1311T in diverse populations. Only 1 of 22 male subjects from Mediterranean countries who had the G6PD Mediterranean-563T genotype had a C at nucleotide 1311, which is the more frequent finding in this group. In contrast, both G6PD Mediterranean-563T males from the Indian subcontinent had the usual C at nucleotide 1311. Beutler and Kuhl (1990) interpreted these findings as suggesting that the same mutation at nucleotide 563 arose independently in Europe and in Asia. Similar studies were done by Kurdi-Haidar et al. (1990) in 21 unrelated individuals with G6PD Mediterranean from Saudi Arabia, Iraq, Iran, Jordan, Lebanon, and Israel. All but 1 had the 563 mutation, and, of these, all but 1 had the C-to-T change at nucleotide 1311. Among another 24 unrelated Middle Eastern persons with normal G6PD activity, 4 had the silent mutation at position 1311 in the absence of the deficiency mutation at position 563. Kurdi-Haidar et al. (1990) concluded that most Middle Eastern subjects with the G6PD Mediterranean phenotype have the same mutation as that found in Italy; that the silent mutation is an independent polymorphism in the Middle East, with a frequency of about 0.13; and that the mutation leading to G6PD Mediterranean deficiency probably arose on a chromosome that already carried the silent mutation. In Nepal, Matsuoka et al. (2003) tested 300 males for G6PD deficiency and identified 2 (0.67%) who were G6PD deficient. Compared with normal controls, G6PD activity was 12% and 26%, respectively. Both subjects had the 563C-T substitution of G6PD Mediterranean (ser188 to phe), and both had the silent 1311C-T change. A similar second change has been described in persons living in Mediterranean countries and Middle East countries. However, the form of G6PD Mediterranean found in India and Pakistan has no replacement at nucleotide 1311. Thus, the 2 subjects in Kathmandu, Nepal, would be closer to people in Middle East countries than people in India. Corcoran et al. (1992) described a G6PD mutant biochemically indistinguishable from the common variety due to a C-to-T mutation at nucleotide 563. Instead, a C-to-T transition was found at nucleotide 592 in exon 6, changing an arginine residue to a cysteine residue only 10 amino acids downstream from the Mediterranean mutation. The new variant was named G6PD Coimbra (305900.0031). Kaplan et al. (1997) presented data suggesting that the coexistence of Mediterranean type G6PD deficiency with the TA insertion polymorphism of the promoter of the UGT1A1 gene (191740.0011), which is associated with Gilbert syndrome (143500) in adults, is responsible for the development of neonatal hyperbilirubinemia. This is the most devastating clinical consequence of G6PD deficiency; it can be severe and result in kernicterus or even death. Kaplan et al. (1997) found that neither G6PD deficiency nor the polymorphism of UDP glucuronosyltransferase alone increased the incidence of neonatal hyperbilirubinemia, but in combination they did. The authors suggested that this gene interaction may serve as a paradigm of the interaction of benign genetic polymorphisms in the causation of disease. Kaplan et al. (2001) reported 2 premature female neonates heterozygous for the G6PD Mediterranean mutation who presented with severe hyperbilirubinemia requiring exchange transfusions. Both had had normal G6PD biochemical screening tests. (less)
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|
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other
(May 11, 2018)
|
no assertion criteria provided
Method: literature only
|
G6PD MEDITERRANEAN
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000031313.7
First in ClinVar: Apr 04, 2013 Last updated: May 14, 2018 |
Comment on evidence:
See Kirkman et al. (1964), Ben-Bassat and Ben-Ishay (1969), Lenzerini et al. (1969), Testa et al. (1980), and Morelli et al. (1984). A change from … (more)
See Kirkman et al. (1964), Ben-Bassat and Ben-Ishay (1969), Lenzerini et al. (1969), Testa et al. (1980), and Morelli et al. (1984). A change from cytosine to thymine at base position 563 (in exon 6) causes a change from serine to phenylalanine in amino acid position 188 (Vulliamy et al., 1988). De Vita et al. (1989) found that G6PD Mediterranean, G6PD Sassari, and G6PD Cagliari have the same mutational change, resulting from a TCC-to-TTC mutation in exon 6. There is a second silent mutation of TAC-to-TAT at codon 437 in exon 11 (C-to-T at nucleotide 1311; see 305900.0018); both codons code for tyrosine. This mutation is a polymorphism, causes class 2 abnormality, and creates a new MboII site. Beutler and Kuhl (1990) studied the distribution of the nucleotide polymorphism C1311T in diverse populations. Only 1 of 22 male subjects from Mediterranean countries who had the G6PD Mediterranean-563T genotype had a C at nucleotide 1311, which is the more frequent finding in this group. In contrast, both G6PD Mediterranean-563T males from the Indian subcontinent had the usual C at nucleotide 1311. Beutler and Kuhl (1990) interpreted these findings as suggesting that the same mutation at nucleotide 563 arose independently in Europe and in Asia. Similar studies were done by Kurdi-Haidar et al. (1990) in 21 unrelated individuals with G6PD Mediterranean from Saudi Arabia, Iraq, Iran, Jordan, Lebanon, and Israel. All but 1 had the 563 mutation, and, of these, all but 1 had the C-to-T change at nucleotide 1311. Among another 24 unrelated Middle Eastern persons with normal G6PD activity, 4 had the silent mutation at position 1311 in the absence of the deficiency mutation at position 563. Kurdi-Haidar et al. (1990) concluded that most Middle Eastern subjects with the G6PD Mediterranean phenotype have the same mutation as that found in Italy; that the silent mutation is an independent polymorphism in the Middle East, with a frequency of about 0.13; and that the mutation leading to G6PD Mediterranean deficiency probably arose on a chromosome that already carried the silent mutation. In Nepal, Matsuoka et al. (2003) tested 300 males for G6PD deficiency and identified 2 (0.67%) who were G6PD deficient. Compared with normal controls, G6PD activity was 12% and 26%, respectively. Both subjects had the 563C-T substitution of G6PD Mediterranean (ser188 to phe), and both had the silent 1311C-T change. A similar second change has been described in persons living in Mediterranean countries and Middle East countries. However, the form of G6PD Mediterranean found in India and Pakistan has no replacement at nucleotide 1311. Thus, the 2 subjects in Kathmandu, Nepal, would be closer to people in Middle East countries than people in India. Corcoran et al. (1992) described a G6PD mutant biochemically indistinguishable from the common variety due to a C-to-T mutation at nucleotide 563. Instead, a C-to-T transition was found at nucleotide 592 in exon 6, changing an arginine residue to a cysteine residue only 10 amino acids downstream from the Mediterranean mutation. The new variant was named G6PD Coimbra (305900.0031). Kaplan et al. (1997) presented data suggesting that the coexistence of Mediterranean type G6PD deficiency with the TA insertion polymorphism of the promoter of the UGT1A1 gene (191740.0011), which is associated with Gilbert syndrome (143500) in adults, is responsible for the development of neonatal hyperbilirubinemia. This is the most devastating clinical consequence of G6PD deficiency; it can be severe and result in kernicterus or even death. Kaplan et al. (1997) found that neither G6PD deficiency nor the polymorphism of UDP glucuronosyltransferase alone increased the incidence of neonatal hyperbilirubinemia, but in combination they did. The authors suggested that this gene interaction may serve as a paradigm of the interaction of benign genetic polymorphisms in the causation of disease. Kaplan et al. (2001) reported 2 premature female neonates heterozygous for the G6PD Mediterranean mutation who presented with severe hyperbilirubinemia requiring exchange transfusions. Both had had normal G6PD biochemical screening tests. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807662.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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G6PD deficiency
Affected status: unknown
Allele origin:
germline
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FirmaLab, FirmaLab
Accession: SCV000106042.1
First in ClinVar: Mar 17, 2017 Last updated: Mar 17, 2017 |
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Pathogenic
(Jul 14, 2018)
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no assertion criteria provided
Method: clinical testing
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Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV000854728.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Pathogenic
(Mar 16, 2021)
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no assertion criteria provided
Method: clinical testing
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Malaria, susceptibility to
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV001739331.1
First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001976349.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(Dec 30, 2017)
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no assertion criteria provided
Method: curation
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Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: yes
Allele origin:
unknown
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Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Accession: SCV000891507.3
First in ClinVar: Mar 24, 2019 Last updated: Jun 23, 2024 |
Geographic origin: Middle East
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Pathogenic
(May 30, 2024)
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no assertion criteria provided
Method: clinical testing
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G6PD-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004744895.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The G6PD c.563C>T variant is predicted to result in the amino acid substitution p.Ser188Phe. This variant, commonly referred to as the "Mediterranean" allele, has been … (more)
The G6PD c.563C>T variant is predicted to result in the amino acid substitution p.Ser188Phe. This variant, commonly referred to as the "Mediterranean" allele, has been reported to be causative for glucose-6-phosphate dehydrogenase (G6PD) deficiency (see for examples Vulliamy et al. 1988. PubMed ID: 3393536; Yusoff et al. 2002. PubMed ID: 12215013; Moiz et al. 2012. PubMed ID: 22906047). This variant is reported in 1.7% of alleles in individuals of South Asian descent and with a global allele frequency of 0.17% including hundreds of hemizygous individuals and several homozygous individuals. This variant is interpreted as pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741952.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928877.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(Nov 02, 2023)
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no assertion criteria provided
Method: clinical testing
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Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Affected status: yes
Allele origin:
germline
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Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004101082.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
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Comment:
Comment:
The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. However, this variant is the most common cause of G6PD deficiency in the Mediterranean area, the Middle East and the India subcontinent (ClinVar ID: VCV000100057). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22906047 , 24460025 , 3393536). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.49). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
A heterozygous variant in exon 6 of the G6PD gene that results in the amino acid substitution of Phenylalanine for Serine at codon 188 was detected. The observed variant c.563C>T (p.Ser188Phe) was previously been reported in the 1000 genomes, gnomAD and TOPMed databases with MAF of 0.0833%, 0.1479% and 0.0559% respectively. The in silico prediction of the variant is damaging by SIFT, FATHMM and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
Comment:
This variant is also known as c.563C>T, p.Ser188Phe (using the alternative transcripts NM_001042351.3 and NM_001360016.2).This alteration has been previously reported as hemizygous change in patients with hemolytic anemia associated with Glucose 6-phosphate deficiency (PMID: 28067620, 24586352, 11445808, 12768444). Functional studies demonstrate decreased enzyme activity in the circulating erythrocytes of individuals with this variant, increased affinity for G6P and decreased in vitro thermostability (PMID: 9342374, 3393536). It is present in the gnomAD population database at a frequency of 0.23% with 471/204697 in heterozygous state, 6/204697 in homozygous state and 256/204697 in hemizygous state. In silico analyses support a deleterious effect of the c.653C>T (p.Ser218Phe) variant on protein function. Based on the available evidence, the c.653C>T (p.Ser218Phe) variant is classified as Pathogenic.
Comment:
Variant found in unrelated hemizygotes with deficiency, many with anemia, jaundice, and favism, and some with CNSHA (PS4_M, PP4). Phenotype transmitted with variant from mother to son (PP1). Decreased activity in red blood cells (0-33%) (PS3). Predicted to be deleterious by REVEL and SIFT (PP3). Reported as pathogenic by multiple clinical testing groups (PP5). Not found in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1516, Prior_P 0.1).
Comment:
Published functional studies demonstrate decreased enzyme activity in circulating erythrocytes, increased affinity for G6P, and decreased in vitro thermostability (Vulliamy et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23479361, 27535533, 31152693, 33413378, 31322791, 24460025, 3393536, 27884173, 19594365, 24586352, 1978555, 25548459, 28492530, 8611726, 28492532, 27853304, 27108201, 30097005, 31863082, 33069889, 31019026, 31980526, 34272389, 34426522, 33072997, 33083013, 30755392, 12215013, 32535712, 32860008, 33726816, 1978554, 22906047)
Comment:
PS3, PS4, PM1, PP5
Comment:
Variant summary: G6PD c.653C>T (p.Ser218Phe) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal domain (IPR022675) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 183257 control chromosomes in the gnomAD database, including 6 homozygotes. This variant has a high frequency in South Asian population (0.017) in gnomAD. c.653C>T (Also known as G6PD Mediterranean) is a common cause of G6PD deficiency in the Mediterranean area, the Middle East and the India subcontinent (Kurdi-Haidar_1990). c.653C>T has been reported in the literature in multiple individuals affected with severe Glucose 6 Phosphate Dehydrogenase Deficiency (Kurdi-Haidar_1990), neonatal hyperbilirubinaemia (Moiz_2012) and hemolytic anemia (examples: Vulliamy_1988, Similuk_2022, and Naofal_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Vulliamy_1988). The following publications have been ascertained in the context of this evaluation (PMID: 36703223, 35753512, 22906047, 3393536, 1978555). Thirty submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The G6PD c.563C>T; p.Ser188Phe variant (rs5030868), also known as G6PD Mediterranean, is reported in the literature in multiple individuals affected with hemolytic anemia, hyperbilirubinemia and G6PD deficiency (Hellani 2009, Jamornthanyawat 2014, Kaplan 1997, Moiz 2012, Molou 2014, Vulliamy 1988). Functional analyses of the variant protein shows decreased enzyme activity, increased affinity for G6P and decreased in vitro thermostability (Moiz 2012, Molou 2014, Vulliamy 1988). This variant is reported in ClinVar (Variation ID: 100057). This variant is found predominantly in the South Asian population with an allele frequency of 1.7% (331/19,078 alleles, including 4 homozygotes and 211 hemizygotes) in the Genome Aggregation Database. The serine at codon 188 is moderately conserved, but computational analyses predict that this variant is deleterious (REVEL: 0.811). Based on available information, this variant is considered to be pathogenic. References: Hellani A et al. G6PD Mediterranean S188F codon mutation is common among Saudi sickle cell patients and increases the risk of stroke. Genet Test Mol Biomarkers. 2009 Aug;13(4):449-52. Jamornthanyawat N et al. A population survey of the glucose-6-phosphate dehydrogenase (G6PD) 563C>T (Mediterranean) mutation in Afghanistan. PLoS One. 2014 Feb 21;9(2):e88605. Kaplan M et al. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12128-32. Moiz B et al. Neonatal hyperbilirubinemia in infants with G6PD c.563C > T Variant. BMC Pediatr. 2012 Aug 20;12:126. Molou E et al. Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency in Greek newborns: the Mediterranean C563T mutation screening. Scand J Clin Lab Invest. 2014 Apr;74(3):259-63. Vulliamy TJ et al. Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5171-5.
Comment:
The missense variant c.563C>T(p.Ser188Phe) in G6PD gene has been observed in individual(s) with G6PD deficiency (Thedsawad A, et. al., 2022;Arunachalam AK, et. al., 2020; AlJaouni et.al., 2011; Jamornthanyawat et. al., 2014). Experimental studies have shown that this missense change affects G6PD function (Molouet. al., 2014). It is commonly reported in individuals of Mediterranean, Middle Eastern, or Indian ancestry (AlJaouni et. al., 2011;Jamornthanyawat et. al., 2014). The observed variant has been reported with allele frequency of 0.2 % in gnomAD database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). Computational evidence (Polyphen -Benign , SIFT - damaging and MutationTaster -disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Ser188Phe in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 188 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Comment:
ACMG Criteria: PS3, PS4, PP3, PP5; Variant was found in hemizygous state.
Comment:
The G6PD c.563C>T (p.Ser188Phe) missense variant, also referred to as G6PD Mediterranean, results in the substitution of serine at amino acid position 188 with phenylalanine. Across a selection of the available literature, the variant has been identified in a homozygous state in six probands, in a hemizygous state in 109 probands and in a heterozygous state in 25 probands (PMID: 19594365; 22906047; 23479361; 24460025; 24586352). The c.563C>T variant was reported in seven of 42 controls in a presumed heterozygous state and is reported at a frequency of 0.017450 in the South Asian population of the Genome Aggregation Database. The c.563C>T variant resulted in 0-7% residual enzyme activity in red blood cells compared to wild type and caused decreased thermostability and reduced catalytic activity (PMID: 3393536). Based on the collective evidence, the c.563C>T (p.Ser188Phe) variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency.
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 188 of the G6PD protein (p.Ser188Phe). This variant is present in population databases (rs5030868, gnomAD 1.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with G6PD deficiency (PMID: 1978554, 8611726, 15315792, 16119988, 22018328, 24586352). It is commonly reported in individuals of Mediterranean, Middle Eastern, or Indian ancestry (PMID: 1978554, 8611726, 15315792, 16119988, 22018328, 24586352). ClinVar contains an entry for this variant (Variation ID: 100057). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PD protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PD function (PMID: 3393536, 22906047, 24460025). For these reasons, this variant has been classified as Pathogenic.
Comment:
ACMG categories: PS3,PM1,PP3,PP5,BP1
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with G6PD deficient haemolytic anaemia (favism) (MIM#300908). (I) 0109 - This gene is associated with X-linked recessive disease. Hemizygous males and homozygous females are commonly affected; however, some heterozygous female carriers can also be affected depending on X-inactivation. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (203 heterozygotes, 6 homozygotes, 256 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glucose-6-phosphate dehydrogenase NAD binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is reported as one of the most common severe pathogenic variants in this gene (ClinVar, LOVD, PMID: 27853304). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The variant has been shown to result in highly impaired enzyme activity (PMID: 3393536, PMID: 7211845). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
G6PD: PP1:Strong, PS4, PS3:Moderate
Comment:
The G6PD c.563C>T variant is predicted to result in the amino acid substitution p.Ser188Phe. This variant, commonly referred to as the "Mediterranean" allele, has been reported to be causative for glucose-6-phosphate dehydrogenase (G6PD) deficiency (see for examples Vulliamy et al. 1988. PubMed ID: 3393536; Yusoff et al. 2002. PubMed ID: 12215013; Moiz et al. 2012. PubMed ID: 22906047). This variant is reported in 1.7% of alleles in individuals of South Asian descent and with a global allele frequency of 0.17% including hundreds of hemizygous individuals and several homozygous individuals. This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This variant in exon 6 of the G6PD gene results in the amino acid substitution from Serine to Phenylalanine at codon 188 (p.Ser188Phe) with the sequence change of c.653C>T (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. This variant is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This variant has previously been reported for Anemia, Nonspherocytic Hemolytic, Due to G6pd Deficiency by T J Vulliamy et al., 1988. The Missense Variants Z-Score for this variant is 2.60. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. This variant has been reported six individuals in homozygous condition, in 109 individuals in hemizygous condition and 25 individuals in heterozygous conditions. (Hellani et al. 2009; PMID: 19594365), (Moiz et al. 2012; PMID: 22906047), (Santana et al. 2013; PMID: 23479361), (Molou et al. 2014; PMID: 24460025) and (Jamornthanyawat et al. 2014; PMID: 24586352).
Comment:
The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. However, this variant is the most common cause of G6PD deficiency in the Mediterranean area, the Middle East and the India subcontinent (ClinVar ID: VCV000100057). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22906047 , 24460025 , 3393536). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.49). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
A heterozygous variant in exon 6 of the G6PD gene that results in the amino acid substitution of Phenylalanine for Serine at codon 188 was detected. The observed variant c.563C>T (p.Ser188Phe) was previously been reported in the 1000 genomes, gnomAD and TOPMed databases with MAF of 0.0833%, 0.1479% and 0.0559% respectively. The in silico prediction of the variant is damaging by SIFT, FATHMM and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
Comment:
This variant is also known as c.563C>T, p.Ser188Phe (using the alternative transcripts NM_001042351.3 and NM_001360016.2).This alteration has been previously reported as hemizygous change in patients with hemolytic anemia associated with Glucose 6-phosphate deficiency (PMID: 28067620, 24586352, 11445808, 12768444). Functional studies demonstrate decreased enzyme activity in the circulating erythrocytes of individuals with this variant, increased affinity for G6P and decreased in vitro thermostability (PMID: 9342374, 3393536). It is present in the gnomAD population database at a frequency of 0.23% with 471/204697 in heterozygous state, 6/204697 in homozygous state and 256/204697 in hemizygous state. In silico analyses support a deleterious effect of the c.653C>T (p.Ser218Phe) variant on protein function. Based on the available evidence, the c.653C>T (p.Ser218Phe) variant is classified as Pathogenic.
Comment:
Variant found in unrelated hemizygotes with deficiency, many with anemia, jaundice, and favism, and some with CNSHA (PS4_M, PP4). Phenotype transmitted with variant from mother to son (PP1). Decreased activity in red blood cells (0-33%) (PS3). Predicted to be deleterious by REVEL and SIFT (PP3). Reported as pathogenic by multiple clinical testing groups (PP5). Not found in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1516, Prior_P 0.1).
Comment:
Published functional studies demonstrate decreased enzyme activity in circulating erythrocytes, increased affinity for G6P, and decreased in vitro thermostability (Vulliamy et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23479361, 27535533, 31152693, 33413378, 31322791, 24460025, 3393536, 27884173, 19594365, 24586352, 1978555, 25548459, 28492530, 8611726, 28492532, 27853304, 27108201, 30097005, 31863082, 33069889, 31019026, 31980526, 34272389, 34426522, 33072997, 33083013, 30755392, 12215013, 32535712, 32860008, 33726816, 1978554, 22906047)
Comment:
PS3, PS4, PM1, PP5
Comment:
Variant summary: G6PD c.653C>T (p.Ser218Phe) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal domain (IPR022675) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 183257 control chromosomes in the gnomAD database, including 6 homozygotes. This variant has a high frequency in South Asian population (0.017) in gnomAD. c.653C>T (Also known as G6PD Mediterranean) is a common cause of G6PD deficiency in the Mediterranean area, the Middle East and the India subcontinent (Kurdi-Haidar_1990). c.653C>T has been reported in the literature in multiple individuals affected with severe Glucose 6 Phosphate Dehydrogenase Deficiency (Kurdi-Haidar_1990), neonatal hyperbilirubinaemia (Moiz_2012) and hemolytic anemia (examples: Vulliamy_1988, Similuk_2022, and Naofal_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Vulliamy_1988). The following publications have been ascertained in the context of this evaluation (PMID: 36703223, 35753512, 22906047, 3393536, 1978555). Thirty submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The G6PD c.563C>T; p.Ser188Phe variant (rs5030868), also known as G6PD Mediterranean, is reported in the literature in multiple individuals affected with hemolytic anemia, hyperbilirubinemia and G6PD deficiency (Hellani 2009, Jamornthanyawat 2014, Kaplan 1997, Moiz 2012, Molou 2014, Vulliamy 1988). Functional analyses of the variant protein shows decreased enzyme activity, increased affinity for G6P and decreased in vitro thermostability (Moiz 2012, Molou 2014, Vulliamy 1988). This variant is reported in ClinVar (Variation ID: 100057). This variant is found predominantly in the South Asian population with an allele frequency of 1.7% (331/19,078 alleles, including 4 homozygotes and 211 hemizygotes) in the Genome Aggregation Database. The serine at codon 188 is moderately conserved, but computational analyses predict that this variant is deleterious (REVEL: 0.811). Based on available information, this variant is considered to be pathogenic. References: Hellani A et al. G6PD Mediterranean S188F codon mutation is common among Saudi sickle cell patients and increases the risk of stroke. Genet Test Mol Biomarkers. 2009 Aug;13(4):449-52. Jamornthanyawat N et al. A population survey of the glucose-6-phosphate dehydrogenase (G6PD) 563C>T (Mediterranean) mutation in Afghanistan. PLoS One. 2014 Feb 21;9(2):e88605. Kaplan M et al. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12128-32. Moiz B et al. Neonatal hyperbilirubinemia in infants with G6PD c.563C > T Variant. BMC Pediatr. 2012 Aug 20;12:126. Molou E et al. Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency in Greek newborns: the Mediterranean C563T mutation screening. Scand J Clin Lab Invest. 2014 Apr;74(3):259-63. Vulliamy TJ et al. Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5171-5.
Comment:
The missense variant c.563C>T(p.Ser188Phe) in G6PD gene has been observed in individual(s) with G6PD deficiency (Thedsawad A, et. al., 2022;Arunachalam AK, et. al., 2020; AlJaouni et.al., 2011; Jamornthanyawat et. al., 2014). Experimental studies have shown that this missense change affects G6PD function (Molouet. al., 2014). It is commonly reported in individuals of Mediterranean, Middle Eastern, or Indian ancestry (AlJaouni et. al., 2011;Jamornthanyawat et. al., 2014). The observed variant has been reported with allele frequency of 0.2 % in gnomAD database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). Computational evidence (Polyphen -Benign , SIFT - damaging and MutationTaster -disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Ser188Phe in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 188 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Comment:
ACMG Criteria: PS3, PS4, PP3, PP5; Variant was found in hemizygous state.
Comment:
The G6PD c.563C>T (p.Ser188Phe) missense variant, also referred to as G6PD Mediterranean, results in the substitution of serine at amino acid position 188 with phenylalanine. Across a selection of the available literature, the variant has been identified in a homozygous state in six probands, in a hemizygous state in 109 probands and in a heterozygous state in 25 probands (PMID: 19594365; 22906047; 23479361; 24460025; 24586352). The c.563C>T variant was reported in seven of 42 controls in a presumed heterozygous state and is reported at a frequency of 0.017450 in the South Asian population of the Genome Aggregation Database. The c.563C>T variant resulted in 0-7% residual enzyme activity in red blood cells compared to wild type and caused decreased thermostability and reduced catalytic activity (PMID: 3393536). Based on the collective evidence, the c.563C>T (p.Ser188Phe) variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency.
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 188 of the G6PD protein (p.Ser188Phe). This variant is present in population databases (rs5030868, gnomAD 1.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with G6PD deficiency (PMID: 1978554, 8611726, 15315792, 16119988, 22018328, 24586352). It is commonly reported in individuals of Mediterranean, Middle Eastern, or Indian ancestry (PMID: 1978554, 8611726, 15315792, 16119988, 22018328, 24586352). ClinVar contains an entry for this variant (Variation ID: 100057). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PD protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PD function (PMID: 3393536, 22906047, 24460025). For these reasons, this variant has been classified as Pathogenic.
Comment:
ACMG categories: PS3,PM1,PP3,PP5,BP1
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with G6PD deficient haemolytic anaemia (favism) (MIM#300908). (I) 0109 - This gene is associated with X-linked recessive disease. Hemizygous males and homozygous females are commonly affected; however, some heterozygous female carriers can also be affected depending on X-inactivation. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (203 heterozygotes, 6 homozygotes, 256 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glucose-6-phosphate dehydrogenase NAD binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is reported as one of the most common severe pathogenic variants in this gene (ClinVar, LOVD, PMID: 27853304). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The variant has been shown to result in highly impaired enzyme activity (PMID: 3393536, PMID: 7211845). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
G6PD: PP1:Strong, PS4, PS3:Moderate
Comment:
The G6PD c.563C>T variant is predicted to result in the amino acid substitution p.Ser188Phe. This variant, commonly referred to as the "Mediterranean" allele, has been reported to be causative for glucose-6-phosphate dehydrogenase (G6PD) deficiency (see for examples Vulliamy et al. 1988. PubMed ID: 3393536; Yusoff et al. 2002. PubMed ID: 12215013; Moiz et al. 2012. PubMed ID: 22906047). This variant is reported in 1.7% of alleles in individuals of South Asian descent and with a global allele frequency of 0.17% including hundreds of hemizygous individuals and several homozygous individuals. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The genomic landscape of rare disorders in the Middle East. | El Naofal M | Genome medicine | 2023 | PMID: 36703223 |
| Cut-off values for diagnosis of G6PD deficiency by flow cytometry in Thai population. | Thedsawad A | Annals of hematology | 2022 | PMID: 35840819 |
| Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations. | Similuk MN | The Journal of allergy and clinical immunology | 2022 | PMID: 35753512 |
| Acute Hemolytic Anemia Caused by G6PD Deficiency in Children in Mayotte: A Frequent and Severe Complication. | Boyadjian M | Journal of pediatric hematology/oncology | 2022 | PMID: 34966093 |
| Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
| Molecular Characterization of G6PD Deficiency: Report of Three Novel G6PD Variants. | Arunachalam AK | Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion | 2020 | PMID: 32425388 |
| Genotyping of Malaysian G6PD-deficient neonates by reverse dot blot flow-through hybridisation. | Alina MF | Journal of human genetics | 2020 | PMID: 31863082 |
| Incidence of Glucose-6-Phosphate Dehydrogenase Deficiency among Swedish Newborn Infants. | Ohlsson A | International journal of neonatal screening | 2019 | PMID: 33072997 |
| Genotype-Phenotype Correlations of Glucose-6-Phosphate-Deficient Variants Throughout an Activity Distribution. | Powers JL | The journal of applied laboratory medicine | 2018 | PMID: 33636823 |
| Genetic Epidemiology of Glucose-6-Phosphate Dehydrogenase Deficiency in the Arab World. | Doss CG | Scientific reports | 2016 | PMID: 27853304 |
| Favism, the commonest form of severe hemolytic anemia in Palestinian children, varies in severity with three different variants of G6PD deficiency within the same community. | Reading NS | Blood cells, molecules & diseases | 2016 | PMID: 27519946 |
| Field trial evaluation of the performances of point-of-care tests for screening G6PD deficiency in Cambodia. | Roca-Feltrer A | PloS one | 2014 | PMID: 25541721 |
| A population survey of the glucose-6-phosphate dehydrogenase (G6PD) 563C>T (Mediterranean) mutation in Afghanistan. | Jamornthanyawat N | PloS one | 2014 | PMID: 24586352 |
| Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency in Greek newborns: the Mediterranean C563T mutation screening. | Molou E | Scandinavian journal of clinical and laboratory investigation | 2014 | PMID: 24460025 |
| Glucose-6-phosphate dehydrogenase deficiency in Italian blood donors: prevalence and molecular defect characterization. | Maffi D | Vox sanguinis | 2014 | PMID: 24134566 |
| Glucose-6-phosphate dehydrogenase deficient variants are associated with reduced susceptibility to malaria in the Brazilian Amazon. | Santana MS | Transactions of the Royal Society of Tropical Medicine and Hygiene | 2013 | PMID: 23479361 |
| Three new mutations account for the prevalence of glucose 6 phosphate deshydrogenase (G6PD) deficiency in Tunisia. | Bendaoud B | Pathologie-biologie | 2013 | PMID: 22552160 |
| Five novel glucose-6-phosphate dehydrogenase deficiency haplotypes correlating with disease severity. | Dallol A | Journal of translational medicine | 2012 | PMID: 23006493 |
| Molecular characterization of glucose-6-phosphate dehydrogenase deficiency among Jordanians. | Al-Sweedan SA | Acta haematologica | 2012 | PMID: 22906837 |
| Neonatal hyperbilirubinemia in infants with G6PD c.563C > T Variant. | Moiz B | BMC pediatrics | 2012 | PMID: 22906047 |
| Molecular heterogeneity of glucose-6-phosphate dehydrogenase deficiency in Gaza Strip Palestinians. | Sirdah M | Blood cells, molecules & diseases | 2012 | PMID: 22770933 |
| Molecular characterization of glucose-6-phosphate dehydrogenase deficient variants in Baghdad city - Iraq. | Al-Musawi BM | BMC blood disorders | 2012 | PMID: 22452742 |
| Glucose-6-phosphate dehydrogenase (G6PD) mutations database: review of the "old" and update of the new mutations. | Minucci A | Blood cells, molecules & diseases | 2012 | PMID: 22293322 |
| Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in Jeddah, Kingdom of Saudi Arabia. | Al-Jaouni SK | BMC research notes | 2011 | PMID: 22018328 |
| Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in Pakistani population. | Moiz B | International journal of laboratory hematology | 2011 | PMID: 21507207 |
| G6PD Mediterranean S188F codon mutation is common among Saudi sickle cell patients and increases the risk of stroke. | Hellani A | Genetic testing and molecular biomarkers | 2009 | PMID: 19594365 |
| Molecular variants of G6PD deficiency among certain tribal communities of Orissa, India. | Nishank SS | Annals of human biology | 2008 | PMID: 18568599 |
| Molecular characterization of erythrocyte glucose-6-phosphate dehydrogenase deficiency in Tunisia. | Daoud BB | Pathologie-biologie | 2008 | PMID: 18226470 |
| Glucose-6-phosphate dehydrogenase mutations in Mon and Burmese of southern Myanmar. | Nuchprayoon I | Journal of human genetics | 2008 | PMID: 18046504 |
| Characterization of G6PD deficiency in southern Croatia: description of a new variant, G6PD Split. | Barišić M | Journal of human genetics | 2005 | PMID: 16143877 |
| Molecular characterization of glucose-6-phosphate dehydrogenase gene defect in the Kuwaiti population. | Alfadhli S | Archives of pathology & laboratory medicine | 2005 | PMID: 16119988 |
| Molecular heterogeneity of glucose-6-phosphate dehydrogenase (G6PD) variants in the south of Thailand and identification of a novel variant (G6PD Songklanagarind). | Laosombat V | Blood cells, molecules & diseases | 2005 | PMID: 15727905 |
| In silico prediction of the deleterious effect of a mutation: proceed with caution in clinical genetics. | Tchernitchko D | Clinical chemistry | 2004 | PMID: 15502081 |
| Molecular basis of G6PD deficiency in India. | Sukumar S | Blood cells, molecules & diseases | 2004 | PMID: 15315792 |
| Two cases of glucose-6-phosphate dehydrogenase-deficient Nepalese belonging to the G6PD Mediterranean-type, not India-Pakistan sub-type but Mediterranean-Middle East sub-type. | Matsuoka H | Journal of human genetics | 2003 | PMID: 12768444 |
| Glucose-6-phosphate dehydrogenase (G6PD) variants in Malaysian Malays. | Ainoon O | Human mutation | 2003 | PMID: 12497642 |
| Glucose-6-phosphate dehydrogenase deficiency in Portugal: biochemical and mutational profiles, heterogeneity, and haplotype association. | Rodrigues MO | Blood cells, molecules & diseases | 2002 | PMID: 12064920 |
| Acute hemolysis and severe neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes. | Kaplan M | The Journal of pediatrics | 2001 | PMID: 11445808 |
| Molecular heterogeneity of the glucose-6-phosphate dehydrogenase deficiency in the Hellenic population. | Menounos P | Human heredity | 2000 | PMID: 10782016 |
| Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. | Kaplan M | Proceedings of the National Academy of Sciences of the United States of America | 1997 | PMID: 9342374 |
| Genetic heterogeneity of glucose-6-phosphate dehydrogenase deficiency in south-east Sicily. | Cittadella R | Annals of human genetics | 1997 | PMID: 9250351 |
| Molecular characterization of G6PD deficiency in Southern Italy: heterogeneity, correlation genotype-phenotype and description of a new variant (G6PD Neapolis). | Alfinito F | British journal of haematology | 1997 | PMID: 9233561 |
| Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in Brazil. | Saad ST | Human heredity | 1997 | PMID: 9017974 |
| Multiple G6PD mutations are associated with a clinical and biochemical phenotype similar to that of G6PD Mediterranean. | Cappellini MD | Blood | 1996 | PMID: 8611726 |
| Biochemical characteristics of four common molecular variants in glucose-6-phosphate dehydrogenase-deficient Chinese in Singapore. | Saha N | Human heredity | 1995 | PMID: 7590755 |
| Molecular genetics of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Spain: identification of two new point mutations in the G6PD gene. | Rovira A | British journal of haematology | 1995 | PMID: 7577654 |
| At least five polymorphic mutants account for the prevalence of glucose-6-phosphate dehydrogenase deficiency in Algeria. | Nafa K | Human genetics | 1994 | PMID: 7959686 |
| Genetic heterogeneity of glucose-6-phosphate dehydrogenase deficiency revealed by single-strand conformation and sequence analysis. | Calabrò V | American journal of human genetics | 1993 | PMID: 8447319 |
| Molecular analysis of G6PD variants in northern Italy: a study on the population from the Ferrara district. | Ninfali P | Human genetics | 1993 | PMID: 8370579 |
| Molecular heterogeneity underlying the G6PD Mediterranean phenotype. | Corcoran CM | Human genetics | 1992 | PMID: 1551674 |
| Molecular genetics of the glucose-6-phosphate dehydrogenase (G6PD) Mediterranean variant and description of a new G6PD mutant, G6PD Andalus1361A. | Vives-Corrons JL | American journal of human genetics | 1990 | PMID: 2393028 |
| Common glucose-6-phosphate dehydrogenase (G6PD) variants from the Italian population: biochemical and molecular characterization. | Viglietto G | Annals of human genetics | 1990 | PMID: 2321910 |
| Genetic heterogeneity at the glucose-6-phosphate dehydrogenase locus in southern Italy: a study on a population from the Matera district. | Calabrò V | Human genetics | 1990 | PMID: 2253938 |
| Origin and spread of the glucose-6-phosphate dehydrogenase variant (G6PD-Mediterranean) in the Middle East. | Kurdi-Haidar B | American journal of human genetics | 1990 | PMID: 1978555 |
| The NT 1311 polymorphism of G6PD: G6PD Mediterranean mutation may have originated independently in Europe and Asia. | Beutler E | American journal of human genetics | 1990 | PMID: 1978554 |
| Linkage between a PvuII restriction fragment length polymorphism and G6PD A-202A/376G: evidence for a single origin of the common G6PD A- mutation. | Beutler E | Human genetics | 1990 | PMID: 1972698 |
| Two point mutations are responsible for G6PD polymorphism in Sardinia. | De Vita G | American journal of human genetics | 1989 | PMID: 2912069 |
| G6PD mahidol, a common deficient variant in South East Asia is caused by a (163)glycine----serine mutation. | Vulliamy TJ | Nucleic acids research | 1989 | PMID: 2503817 |
| Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. | Vulliamy TJ | Proceedings of the National Academy of Sciences of the United States of America | 1988 | PMID: 3393536 |
| G6PD Cagliari: a new low activity glucose 6-phosphate dehydrogenase variant characterized by enhanced intracellular lability. | Morelli A | Human genetics | 1984 | PMID: 6698555 |
| 2-deoxy-glucose-6-phosphate utilization in the study of glucose-6-phosphate dehydrogenase mosaicism. | Ferraris AM | American journal of human genetics | 1981 | PMID: 7211845 |
| Variants of erythrocyte glucose-6-phosphate dehydrogenase (G6PD) in Bulgarian populations. | Shatskaya TL | Human genetics | 1980 | PMID: 7390473 |
| Genetic heterogeneity of glucose 6-phosphate dehydrogenase deficiency in Sardinia. | Testa U | Human genetics | 1980 | PMID: 7203486 |
| Hereditary hemolytic anemia associated with glucose-6-phosphate dehydrogenase deficiency (Mediterranean type). | Benbassat J | Israel journal of medical sciences | 1969 | PMID: 5369703 |
| Characterization of glucose-6-phosphate dehydrogenase variants. I. Occurrence of a G6PD Seattle-like variant in Sardinia and its interaction with the G6PD Mediterranean variant. | Lenzerini L | American journal of human genetics | 1969 | PMID: 5305539 |
| A new structural variant of glucose-6-phosphate dehydrogenase with a high production rate (G6PD Hektoen). | Dern RJ | The Journal of laboratory and clinical medicine | 1969 | PMID: 4974311 |
| Variants of red cell glucose-6-phosphate dehydrogenase among Asiatic Indians. | Azevedo E | Annals of human genetics | 1968 | PMID: 5673160 |
| In vivo lability of glucose-6-phosphate dehydrogenase in GdA- and GdMediterranean deficiency. | Piomelli S | The Journal of clinical investigation | 1968 | PMID: 5641629 |
| FUNCTIONALLY ABNORMAL GLUCOSE-6-PHOSPHATE DEHYDROGENASES. | KIRKMAN HN | Cold Spring Harbor symposia on quantitative biology | 1964 | PMID: 14278484 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=G6PD | - | - | - | - |
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Text-mined citations for rs5030868 ...
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Record last updated Nov 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.