Variant summary: The HBB c.90C>T (p.Gly30Gly) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict that this varaint may create a novel 5' splicing donor site and a frameshift change. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/121334 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). However, this variant has been reported as a mild beta+ type mutation in numerous patients with beta thalassemia intermedia in homozygous and compound heterozygous states. Ithanet lists variant as a globin gene causative mutation. Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.90C>T (p.Gly30=)
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.
(7)
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000518.5(HBB):c.90C>T (p.Gly30=)
Variation ID: 38682 Accession: VCV000038682.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5226932 (GRCh38) [ NCBI UCSC ] 11: 5248162 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 17, 2018 Feb 4, 2024 Aug 29, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.90C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Gly30= synonymous NC_000011.10:g.5226932G>A NC_000011.9:g.5248162G>A NG_000007.3:g.70684C>T NG_042296.1:g.463G>A NG_046672.1:g.4867G>A NG_059281.1:g.5140C>T LRG_1232:g.5140C>T LRG_1232t1:c.90C>T LRG_1232p1:p.Gly30= - Protein change
- -
- Other names
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CD 29 (C>T) or IVS I (-3) GGC>GGT (Gly>Gly)
- Canonical SPDI
- NC_000011.10:5226931:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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.
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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| HBB | - | - |
GRCh38 GRCh37 |
22 | 1834 | |
| LOC106099062 | - | - | - | GRCh38 | - | 862 |
| LOC107133510 | - | - | - | GRCh38 | - | 1784 |
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 (4) |
criteria provided, single submitter
|
Dec 7, 2016 | RCV000588766.6 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Aug 29, 2023 | RCV001269729.6 |
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. |
|
|---|---|---|---|---|---|
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Pathogenic
(Dec 07, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
beta Thalassemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697153.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The HBB c.90C>T (p.Gly30Gly) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a … (more)
Variant summary: The HBB c.90C>T (p.Gly30Gly) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict that this varaint may create a novel 5' splicing donor site and a frameshift change. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/121334 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). However, this variant has been reported as a mild beta+ type mutation in numerous patients with beta thalassemia intermedia in homozygous and compound heterozygous states. Ithanet lists variant as a globin gene causative mutation. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Uncertain significance
(Aug 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004219897.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The HBB c.90C>T (p.Gly30=) synonymous variant has been reported in the published literature in individuals affected with beta(+) thalassemia (PMID: 7786794 (1995), 3828533 (1987)). Additionally, … (more)
The HBB c.90C>T (p.Gly30=) synonymous variant has been reported in the published literature in individuals affected with beta(+) thalassemia (PMID: 7786794 (1995), 3828533 (1987)). Additionally, this variant might affect splicing and this might cause the observed beta(+) phenotype in one study (PMID: 3828533 (1987)), and low expression levels of hemoglobin in another study (PMID: 7786794 (1995)). The frequency of this variant in the general population, 0.000004 (1/251342 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on HBB mRNA splicing yielded inconclusive findings . Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
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Likely pathogenic
(Jan 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449944.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
|
|
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Likely pathogenic
(May 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003834203.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Nov 25, 2019)
|
no assertion criteria provided
Method: curation
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
|
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Accession: SCV001244430.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
|
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Pathogenic
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Beta thalassemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002091592.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
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Pathogenic
(Oct 15, 2021)
|
no assertion criteria provided
Method: clinical testing
|
beta Thalassemia
Affected status: yes
Allele origin:
germline
|
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV002029166.1
First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021 |
|
Comment:
Comment:
The HBB c.90C>T (p.Gly30=) synonymous variant has been reported in the published literature in individuals affected with beta(+) thalassemia (PMID: 7786794 (1995), 3828533 (1987)). Additionally, this variant might affect splicing and this might cause the observed beta(+) phenotype in one study (PMID: 3828533 (1987)), and low expression levels of hemoglobin in another study (PMID: 7786794 (1995)). The frequency of this variant in the general population, 0.000004 (1/251342 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on HBB mRNA splicing yielded inconclusive findings . Based on the available information, we are unable to determine the clinical significance of this variant.
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:
Variant summary: The HBB c.90C>T (p.Gly30Gly) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict that this varaint may create a novel 5' splicing donor site and a frameshift change. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/121334 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). However, this variant has been reported as a mild beta+ type mutation in numerous patients with beta thalassemia intermedia in homozygous and compound heterozygous states. Ithanet lists variant as a globin gene causative mutation. Taken together, this variant is classified as pathogenic.
Comment:
The HBB c.90C>T (p.Gly30=) synonymous variant has been reported in the published literature in individuals affected with beta(+) thalassemia (PMID: 7786794 (1995), 3828533 (1987)). Additionally, this variant might affect splicing and this might cause the observed beta(+) phenotype in one study (PMID: 3828533 (1987)), and low expression levels of hemoglobin in another study (PMID: 7786794 (1995)). The frequency of this variant in the general population, 0.000004 (1/251342 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on HBB mRNA splicing yielded inconclusive findings . Based on the available information, we are unable to determine the clinical significance of this variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Interaction of an α-Globin Gene Triplication with β-Globin Gene Mutations in Iranian Patients with β-Thalassemia Intermedia. | Farashi S | Hemoglobin | 2015 | PMID: 26084319 |
| Molecular Basis of β-Thalassemia in the Population of the Aegean Region of Turkey: Identification of A Novel Deletion Mutation. | Ozkinay F | Hemoglobin | 2015 | PMID: 26076395 |
| Broader spectrum of β-thalassemia mutations in Oman: regional distribution and comparison with neighboring countries. | Hassan SM | Hemoglobin | 2015 | PMID: 25677748 |
| Mutations of a country: a mutation review of single gene disorders in the United Arab Emirates (UAE). | Al-Gazali L | Human mutation | 2010 | PMID: 20437613 |
| Beta-thalassaemia intermedia in Lebanon. | Qatanani M | European journal of haematology | 2000 | PMID: 10776695 |
| Haemoglobin Dhofar is linked to the codon 29 C-->T (IVS-1 nt-3) splice mutation which causes beta+ thalassaemia. | Williamson D | British journal of haematology | 1995 | PMID: 7786794 |
| The molecular basis of beta-thalassemia in Lebanon: application to prenatal diagnosis. | Chehab FF | Blood | 1987 | PMID: 3828533 |
| https://ithanet.eu/db/ithagenes?ithaID=96 | - | - | - | - |
Text-mined citations for rs35578002 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Mar 17, 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.