NM_001360016.2(G6PD):c.1004C>A (p.Ala335Asp) AND Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 12, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001379702.8

Allele description [Variation Report for NM_001360016.2(G6PD):c.1004C>A (p.Ala335Asp)]

NM_001360016.2(G6PD):c.1004C>A (p.Ala335Asp)

Gene:

G6PD:glucose-6-phosphate dehydrogenase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_001360016.2(G6PD):c.1004C>A (p.Ala335Asp)

Other names:

G6PD Fushan

HGVS:

NC_000023.11:g.154532989G>T
NG_009015.2:g.19584C>A
NM_000402.4:c.1094C>A
NM_001042351.3:c.1004C>A
NM_001360016.2:c.1004C>AMANE SELECT
NP_000393.4:p.Ala365Asp
NP_001035810.1:p.Ala335Asp
NP_001346945.1:p.Ala335Asp
NC_000023.10:g.153761204G>T
NM_001042351.1:c.1004C>A

Protein change:

A335D

Links:

dbSNP: rs1557229854

NCBI 1000 Genomes Browser:

rs1557229854

Molecular consequence:

NM_000402.4:c.1094C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042351.3:c.1004C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001360016.2:c.1004C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Synonyms:: Hemolytic anemia due to G6PD deficiency; Favism, susceptibility to; Class I glucose-6-phosphate dehydrogenase deficiency
Identifiers:: MONDO: MONDO:0010480; MedGen: C2720289; Orphanet: 466026; OMIM: 300908

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001577550	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 29, 2020)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11499668, 16927025, 20602793, 21677401, 22293322, 25548459, 2606066, 5775246, 15625830, 7803800, 28492532
SCV002599354	Dunham Lab, University of Washington	criteria provided, single submitter (Bayesian ACMG Guidelines, 2018)	Pathogenic (Aug 12, 2022)	unknown	curation	PubMed (6) [See all records that cite these PMIDs] 30045279, 7803800, 31489982, 15625830, 16607506, 29300386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001577550

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 29, 2020)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV002599354

Dunham Lab, University of Washington

criteria provided, single submitter

(Bayesian ACMG Guidelines, 2018)

Pathogenic
(Aug 12, 2022)

unknown

curation

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Distribution of glucose-6-phosphate dehydrogenase mutations in Southeast Asia.

Iwai K, Hirono A, Matsuoka H, Kawamoto F, Horie T, Lin K, Tantular IS, Dachlan YP, Notopuro H, Hidayah NI, Salim AM, Fujii H, Miwa S, Ishii A.

Hum Genet. 2001 Jun;108(6):445-9.

PubMed [citation]

PMID:: 11499668

Further investigations of glucose-6-phosphate dehydrogenase variants in Flores Island, eastern Indonesia.

Kawamoto F, Matsuoka H, Kanbe T, Tantular IS, Pusarawati S, Kerong HI, Damianus W, Mere D, Dachlan YP.

J Hum Genet. 2006;51(11):952-957. doi: 10.1007/s10038-006-0044-y. Epub 2006 Aug 23.

PubMed [citation]

PMID:: 16927025

See all PubMed Citations (15)

Details of each submission

From Invitae, SCV001577550.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala335 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11499668, 16927025, 20602793, 21677401, 22293322, 25548459, 2606066). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 5775246, 15625830, 7803800). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with aspartic acid at codon 335 of the G6PD protein (p.Ala335Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Dunham Lab, University of Washington, SCV002599354.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

Variant found in unrelated hemizygotes with deficiency, some with anemia (PS4_M, PP4). Decreased activity in red blood cells (11-19%) (PS3). Affects same amino acid as pathogenic 335A>T (ClinVar ID 10363) (PM5). Below expected carrier frequency in gnomAD (PM2). Post_P 0.997 (odds of pathogenicity 3158, Prior_P 0.1).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 30, 2024

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