ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.937G>T (p.Asp313Tyr)
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.
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.
Uncertain significance(3); Benign(8); Likely benign(12)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000169.3(GLA):c.937G>T (p.Asp313Tyr)
Variation ID: 10738 Accession: VCV000010738.67
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101398432 (GRCh38) [ NCBI UCSC ] X: 100653420 (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 Dec 23, 2013 Apr 15, 2024 Nov 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.937G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Asp313Tyr missense NM_001199973.2:c.300+2975C>A intron variant NM_001199974.2:c.177+6610C>A intron variant NR_164783.1:n.1016G>T non-coding transcript variant NC_000023.11:g.101398432C>A NC_000023.10:g.100653420C>A NG_007119.1:g.14532G>T LRG_672:g.14532G>T LRG_672t1:c.937G>T LRG_672p1:p.Asp313Tyr P06280:p.Asp313Tyr - Protein change
- D313Y
- Other names
- -
- Canonical SPDI
- NC_000023.11:101398431:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on protein activity Variation Ontology [VariO:0053]
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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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0.00212 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00212
The Genome Aggregation Database (gnomAD) 0.00308
Exome Aggregation Consortium (ExAC) 0.00313
1000 Genomes Project 30x 0.00166
Trans-Omics for Precision Medicine (TOPMed) 0.00285
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 | ||
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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. |
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GLA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
6 | 1235 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1263 |
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. |
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Conflicting interpretations of pathogenicity; other (10) |
criteria provided, conflicting classifications
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May 18, 2021 | RCV000011486.38 | |
Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 13, 2023 | RCV000035314.25 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 27, 2015 | RCV000172895.12 | |
Benign (1) |
criteria provided, single submitter
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Jan 11, 2018 | RCV000250525.11 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Sep 29, 2022 | RCV000346926.16 | |
Conflicting interpretations of pathogenicity; other (6) |
criteria provided, conflicting classifications
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Nov 10, 2023 | RCV000487818.42 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 19, 2023 | RCV000769536.13 |
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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Likely benign
(Jun 29, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000609890.1
First in ClinVar: Oct 30, 2017 Last updated: Oct 30, 2017 |
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Likely benign
(Jul 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740567.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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other
(Aug 22, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331021.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 5
Sex: mixed
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Benign
(Mar 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000902838.1
First in ClinVar: May 19, 2019 Last updated: May 19, 2019 |
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Likely benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001141977.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Benign
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: no
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440321.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: yes
Allele origin:
germline
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CeMIA
Accession: SCV001571670.2
First in ClinVar: Apr 24, 2021 Last updated: Apr 24, 2021 |
Comment:
The c.937G>T (p.Asp313Tyr) variant, located in exon 6 of the GLA gene, has been previously reported to be associated with Fabry disease (PMID: 20122163, 23393592, … (more)
The c.937G>T (p.Asp313Tyr) variant, located in exon 6 of the GLA gene, has been previously reported to be associated with Fabry disease (PMID: 20122163, 23393592, 26993117, 7504405), however this variant does not lead to severe organ manifestations as seen in genotypes known to be causal for classical FD (PMID: 27059467). Functional studies support that the variant renders the protein unstable at neutral pH resulting in a pseudodeficiency in plasma, but the enzyme was stable at lysosomal pH, which prompts further investigation to detect a second, causative mutation (PMID: 14635108). The variant was identified in seventeen individuals (7 hemizygous males, 10 heterozygous females), in which only thirteen (6 hemizygous males, 7 heterozygous females) were affected with Fabry disease. The presentation of the disease in the patients indicates that the mutation results in a milder phenotype, with later onset of symptoms. Bioinformatic analysis by SIFT and PolyPhen2 algorithms predicted this mutation as deleterious and probably damaging, respectively. It has been detected in 0.304% alleles worldwide (gnomAD database) and its allele frequency is higher than that expected for Fabry disease. Taking all the above into account and according to ACMG Guidelines (Criteria: PM1, PP2, PP3, BS1, BP5) the variant has contradictory interpretation of pathogenicity, therefore is considered as variant of uncertain significance. (less)
Number of individuals with the variant: 17
Sex: mixed
Testing laboratory: CeMIA
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Uncertain significance
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001652719.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
Sex: mixed
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Benign
(Jan 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000318693.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA … (more)
This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
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Likely benign
(Oct 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695753.4
First in ClinVar: Apr 21, 2018 Last updated: Nov 20, 2023 |
Comment:
Variant summary: GLA c.937G>T (p.Asp313Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: GLA c.937G>T (p.Asp313Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 207410 control chromosomes (in the gnomAD database and publication data), including 3 homozygotes and 266 hemizygotes. This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in GLA causing Fabry Disease (0.003 vs 0.005), allowing no clear conclusions about variant significance, though the presence of high numbers of hemizygotes suggests a generally benign role for the variant. In the literature, this variant has been observed in large phenotypic range of patients, from clinically normal to classic Fabry disease patients, including patients with cardiac-, renal and cerebrovascular manifestations. However, in multiple cases co-occurrences with other (potentially) pathogenic variants have been reported, providing supporting evidence for a benign role. Specifically, this variant was found in three male patients with Classical Fabry disease together (i.e. in cis) with other pathogenic missense variants G411D, R112C and C172G; and these latter mutations, but not D313Y, individually showed impaired enzyme activity and were presumably misfolded and/or unstable, resulting in their retention in the endoplasmic reticulum and subsequent proteosome degradation (Guffon_1998, Yasuda_2003). Moreover, in one of the reported families this variant did not co-segregate with disease, did not result in reduced alpha-Gal-A activity or clinical Fabry manifestations in carrier males, neither did the presence of this variant in carrier Fabry females enhance the phenotype of the known causative mutation in the GLA gene (G271S) in this study (Hasholt_2017). In addition, the variant of interest was also found in a female patient (phase is unknown) together with a pathogenic variant c.835C>G (p.Q279E) in an internal LCA sample. Functional studies have shown that D313Y does not disrupt enzyme structure, has >90% residual enzyme activity and is stable at lysosomal pH (4.5), but has ~60% residual enzyme activity at pH 7.4 as it is unstable at this pH, resulting in a pseudodeficiency when measured from plasma (Yasuda_2003). Overall, functional studies suggest that the D313Y variant is a functional polymorphism rather than a disease-causing variant. Several studies reported the variant to be associated with a risk of neurologic involvement, particularly late-onset cerebrovascular disease, white matter lesions and small fiber neuropathy (e.g. Brouns_2010, Lenders_2010, Effraimidis_2020, Von Cossel_2021). In summary, based on the evidence outlined above, though the D313Y variant might be associated with a risk for late-onset neurologic manifestations, it does not cause Fabry disease. The following publications have been ascertained in the context of this evaluation (PMID: 25078086, 20110537, 29044343, 11668641, 20360539, 23219219, 32246457, 7504405, 14680977, 20122163, 9452111, 29037082, 28988177, 23393592, 26415523, 23430502, 29530533, 24829596, 29631605, 33543778, 14635108, 27832731, 32109691, 28276057, 35971858). Eighteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=17) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Nov 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004235158.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
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Likely benign
(Apr 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000900931.4 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024 |
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Benign
(Apr 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000575658.26
First in ClinVar: May 08, 2017 Last updated: Apr 15, 2024 |
Comment:
GLA: BP2, BP5, BS3:Supporting, BS1
Number of individuals with the variant: 1
|
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Likely benign
(Mar 27, 2015)
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criteria provided, single submitter
Method: research
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Sudden unexplained death
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV000223886.2
First in ClinVar: Jun 15, 2015 Last updated: Jun 15, 2015 |
Comment:
The GLA Asp313Tyr variant has been previously reported to be associated with Fabry disease and observed in isolated HCM cases, however this variant is often … (more)
The GLA Asp313Tyr variant has been previously reported to be associated with Fabry disease and observed in isolated HCM cases, however this variant is often identified in combination with another variant which is able to explain the disease phenotype (Eng et al., 1993; Sachdev B et al., 2002; Yasuda M et al., 2003; Monserrat L et al., 2007). The population frequency in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) is 0.003 alleles (275/87762); and the frequency in the European (non-Finnish) sub-population is 0.004 (211/48000). We have identified this variant in a 16 yo boy who had a sudden cardiac arrest with no pre-morbid diagnosis and Greek ethnicity. Post-mortem examination was unremarkable and there is no family history of any cardiac disease. Based on the frequency of the GLA Asp313Tyr variant in 0.4% of the population, we do not expect this variant to cause disease in isolation. We therefore classify this variant as "likely benign". (less)
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Likely benign
(Mar 11, 2015)
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criteria provided, single submitter
Method: research
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Fabry disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: CSER - NEXT Medicine variant annotation
Accession: SCV000212218.1 First in ClinVar: May 20, 2016 Last updated: May 20, 2016 |
Indication for testing: adults with personal and/or family history of colorectal cancer and/or polyps
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Likely benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000302837.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000481401.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
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other
(Dec 27, 2018)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000543768.5
First in ClinVar: Dec 06, 2016 Last updated: Aug 14, 2019 |
|
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Likely benign
(Aug 02, 2012)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000058962.5
First in ClinVar: May 03, 2013 Last updated: Oct 02, 2016 |
Comment:
p.Asp313Tyr in exon 6 of GLA: This variant is not expected to have clinical sign ificance for cardiomyopathy since it has been identified in 0.4% … (more)
p.Asp313Tyr in exon 6 of GLA: This variant is not expected to have clinical sign ificance for cardiomyopathy since it has been identified in 0.4% (29/6728) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/; dbSNP rs28935490). It has been rep orted in patients with clinical manifestations ranging from classic Fabry diseas e to isolated HCM (Eng 1993, Blaydon 2001, Sachdev 2002, Froissart 2003, Yasuda 2003, Morita 2006, Monserrat 2007) and while cell culture studies showed that th e mutant GLA protein retains ~60% of the normal activity, the p.Asp313Tyr varian t renders the protein unstable at neutral pH resulting in a pseudodeficiency in plasma (Yasuda 2003). In males with classic Fabry disease, it usually occurs wit h a second GLA variant (Eng 1993, Yasuda 2003), and is highly likely insufficien t to cause classic Fabry disease in isolation. (less)
Number of individuals with the variant: 19
|
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Likely benign
(Jul 26, 2017)
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criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995806.1
First in ClinVar: Oct 11, 2019 Last updated: Oct 11, 2019 |
Number of individuals with the variant: 1
|
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Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000481400.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Benign
(Mar 03, 2015)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001898477.1
First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021 |
Comment:
The D313Y variant listed below is associated with pseudodeficiency for alpha-galactosidase A activity. D313Y reduces the in vitro activity of the alpha-galactosidase A enzyme to … (more)
The D313Y variant listed below is associated with pseudodeficiency for alpha-galactosidase A activity. D313Y reduces the in vitro activity of the alpha-galactosidase A enzyme to approximately 60-70% of normal. The presence of the D313Y variant does not cause Fabry disease [Froissart et al. (2003) Mol. Genet. Metab. 80 (3):307-14 (PMID: 14680977); Niemann et al. (2013) JIMD Rep 7 :99-102 (PMID: 23430502)].; This variant is associated with the following publications: (PMID: 32246457, 32109691, 32281532, 30477121, 31860127, 31291414, 30830284, 29227985, 28703315, 28988177, 29037082, 28299312, 28276057, 27600940, 29044343, 25382311, 27153395, 26993117, 7504405, 20110537, 23393592, 23935525, 18057066, 14680977, 23430502, 22773828, 18297328, 14635108, 24356988, 22537551, 23219219, 25078086, 21896204, 20122163, 16773563) (less)
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Benign
(Jul 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: yes
Allele origin:
germline
|
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984289.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Benign
(Sep 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Cohesion Phenomics
Accession: SCV003800594.2
First in ClinVar: Feb 13, 2023 Last updated: Apr 15, 2023 |
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Benign
(Nov 03, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885525.6
First in ClinVar: Feb 17, 2019 Last updated: Feb 20, 2024 |
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Uncertain significance
(Jan 01, 2013)
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no assertion criteria provided
Method: literature only
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RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000031718.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 23, 2013 |
Comment on evidence:
This variant, formerly titled FABRY DISEASE, has been reclassified based on the findings of Yasuda et al. (2003). In a German patient with classic Fabry … (more)
This variant, formerly titled FABRY DISEASE, has been reclassified based on the findings of Yasuda et al. (2003). In a German patient with classic Fabry disease (301500), Eng et al. (1993) found a GAT-to-TAT mutation in exon 6 of the GLA gene, resulting in an asp313-to-tyr (D313Y) substitution. Yasuda et al. (2003) found that expression of the D313Y variant in COS-7 cells resulted in 60% residual enzyme activity and that the enzyme was localized to lysosomes. In addition, the D313Y variant was found in 0.45% of 883 normal X chromosomes. Molecular homology modeling showed that the D313Y variant did not markedly disrupt enzyme structure. The variant enzyme was stable at lysosomal pH (4.5), but had decreased activity at neutral pH (7.4). Overall, the findings suggested that the D313Y variant is a functional polymorphism rather than a disease-causing variant. Lenders et al. (2013) noted that the possible pathogenicity of the D313Y variant is controversial. They reported a large family in which 9 females and 1 male carried a heterozygous D313Y mutation; one of the females with the variant was deceased. Seven of the 8 who underwent brain imaging had multifocal white matter lesions, including several young individuals without cardiovascular risk factors. The white matter lesions were primarily subcortical and punctate, but some also were confluent with a periventricular localization. Brain MRI in 2 family members who did not carry the D313Y variant showed no white matter lesions. GLA enzyme activities were normal in carrier leukocytes, but were decreased in plasma. Lyso-Gb3 levels in plasma, which are increased in patients with Fabry disease, were normal. The proband, who carried the D313Y variant, had a peripheral small-fiber neuropathy with decreased intraepithelial nerve fiber density on nerve biopsy. None of the variant carriers had other evidence of Fabry disease, but Lenders et al. (2013) postulated that the D313Y variant may act as a predisposing factor for neurologic manifestations. Niemann et al. (2013) reported a father and daughter with the D313Y variant. The daughter presented with diffuse skin lesions and nonspecific arm pain. Plasma GLA enzyme activity was mildly decreased. Skin biopsy showed keratosis pilaris rubra atrophicans, but no Fabry angioma. Her 53-year-old father had no clinical manifestations of Fabry disease, although his plasma GLA enzyme activity was also decreased. Lyso-Gb3 was below normal in the daughter and undetectable in the father. Niemann et al. (2013) concluded that the D313Y variant is not clinically relevant for Fabry disease. The authors also suggested that pure assessment of GLA activity and even genetic testing is not sufficient for diagnosing Fabry disease. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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X-chromosomal inactivation patterns in women with Fabry disease. | Wagenhäuser L | Molecular genetics & genomic medicine | 2022 | PMID: 35971858 |
Assessment of small fiber neuropathy in patients carrying the non-classical Fabry variant p.D313Y. | von Cossel K | Muscle & nerve | 2021 | PMID: 33543778 |
Is the alpha-galactosidase A variant p.Asp313Tyr (p.D313Y) pathogenic for Fabry disease? A systematic review. | Effraimidis G | Journal of inherited metabolic disease | 2020 | PMID: 32246457 |
The mutation D313Y may be associated with nervous system manifestations in Fabry disease. | Zompola C | Journal of the neurological sciences | 2020 | PMID: 32109691 |
Fabry disease in the Spanish population: observational study with detection of 77 patients. | Vieitez I | Orphanet journal of rare diseases | 2018 | PMID: 29631605 |
Fabry disease revisited: Management and treatment recommendations for adult patients. | Ortiz A | Molecular genetics and metabolism | 2018 | PMID: 29530533 |
Case report: is low α-Gal enzyme activity sufficient to establish the diagnosis of Fabry disease? | Biagini G | Jornal brasileiro de nefrologia | 2017 | PMID: 29044343 |
The D313Y variant in the GLA gene - no evidence of a pathogenic role in Fabry disease. | Hasholt L | Scandinavian journal of clinical and laboratory investigation | 2017 | PMID: 29037082 |
Fabry disease due to D313Y and novel GLA mutations. | Koulousios K | BMJ open | 2017 | PMID: 28988177 |
The mutation p.D313Y is associated with organ manifestation in Fabry disease. | du Moulin M | Clinical genetics | 2017 | PMID: 28276057 |
Screening Fabry's disease in chronic kidney disease patients not on dialysis: a multicenter study. | Yeniçerioğlu Y | Renal failure | 2017 | PMID: 27832731 |
Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease. | Lukas J | Human mutation | 2016 | PMID: 26415523 |
Nationwide study on hypertrophic cardiomyopathy in Iceland: evidence of a MYBPC3 founder mutation. | Adalsteinsdottir B | Circulation | 2014 | PMID: 25078086 |
Idiopathic small fiber neuropathy: phenotype, etiologies, and the search for fabry disease. | Samuelsson K | Journal of clinical neurology (Seoul, Korea) | 2014 | PMID: 24829596 |
Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease. | Niemann M | JIMD reports | 2013 | PMID: 23430502 |
Multifocal white matter lesions associated with the D313Y mutation of the α-galactosidase A gene. | Lenders M | PloS one | 2013 | PMID: 23393592 |
Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young. | De Brabander I | Clinical neurology and neurosurgery | 2013 | PMID: 23219219 |
Atypical case of Wolfram syndrome revealed through targeted exome sequencing in a patient with suspected mitochondrial disease. | Lieber DS | BMC medical genetics | 2012 | PMID: 22226368 |
Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. | Ferri L | Clinical genetics | 2012 | PMID: 21517827 |
Toward a consensus in the laboratory diagnostics of Fabry disease - recommendations of a European expert group. | Gal A | Journal of inherited metabolic disease | 2011 | PMID: 21229318 |
Fabry disease in patients with migraine with aura. | Albano B | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2010 | PMID: 20464614 |
Belgian Fabry study: prevalence of Fabry disease in a cohort of 1000 young patients with cerebrovascular disease. | Brouns R | Stroke | 2010 | PMID: 20360539 |
Frequency of Fabry disease in male and female haemodialysis patients in Spain. | Gaspar P | BMC medical genetics | 2010 | PMID: 20122163 |
Mutations of the GLA gene in young patients with stroke: the PORTYSTROKE study--screening genetic conditions in Portuguese young stroke patients. | Baptista MV | Stroke | 2010 | PMID: 20110537 |
Danon disease: further clinical and molecular heterogeneity. | Sabourdy F | Muscle & nerve | 2009 | PMID: 19373884 |
The pulvinar sign: frequency and clinical correlations in Fabry disease. | Burlina AP | Journal of neurology | 2008 | PMID: 18297328 |
Agalsidase therapy in patients with Fabry disease on renal replacement therapy: a nationwide study in Italy. | Mignani R | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2008 | PMID: 18057066 |
Prevalence of fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy. | Monserrat L | Journal of the American College of Cardiology | 2007 | PMID: 18154965 |
Single-gene mutations and increased left ventricular wall thickness in the community: the Framingham Heart Study. | Morita H | Circulation | 2006 | PMID: 16754800 |
Deficient alpha-galactosidase A activity in plasma but no Fabry disease--a pitfall in diagnosis. | Hoffmann B | Clinical chemistry and laboratory medicine | 2005 | PMID: 16232095 |
Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in the Czech and Slovak population. | Dobrovolny R | Journal of molecular medicine (Berlin, Germany) | 2005 | PMID: 15806320 |
Fabry disease: D313Y is an alpha-galactosidase A sequence variant that causes pseudodeficient activity in plasma. | Froissart R | Molecular genetics and metabolism | 2003 | PMID: 14680977 |
Fabry disease: characterization of alpha-galactosidase A double mutations and the D313Y plasma enzyme pseudodeficiency allele. | Yasuda M | Human mutation | 2003 | PMID: 14635108 |
Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. | Sachdev B | Circulation | 2002 | PMID: 11914245 |
Fabry disease: 20 novel GLA mutations in 35 families. | Blaydon D | Human mutation | 2001 | PMID: 11668641 |
Mutation analysis in 11 French patients with Fabry disease. | Guffon N | Human mutation | 1998 | PMID: 9452111 |
Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. | Eng CM | American journal of human genetics | 1993 | PMID: 7504405 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
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Text-mined citations for rs28935490 ...
HelpRecord last updated Apr 20, 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.