ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.937G>T (p.Asp313Tyr)

gnomAD frequency: 0.00308  dbSNP: rs28935490
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Total submissions: 26
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000035314 SCV000058962 likely benign not specified 2012-08-02 criteria provided, single submitter clinical testing 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 (; 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.
CSER _CC_NCGL, University of Washington RCV000011486 SCV000212218 likely benign Fabry disease 2015-03-11 criteria provided, single submitter research
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute RCV000172895 SCV000223886 likely benign Sudden unexplained death 2015-03-27 criteria provided, single submitter research 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 ( 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".
PreventionGenetics, part of Exact Sciences RCV000035314 SCV000302837 likely benign not specified criteria provided, single submitter clinical testing
Ambry Genetics RCV000250525 SCV000318693 benign Cardiovascular phenotype 2018-01-11 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Eurofins Ntd Llc (ga) RCV000487818 SCV000331021 other not provided 2018-08-22 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000011486 SCV000481400 likely benign Fabry disease 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Laboratory Services, Illumina RCV000346926 SCV000481401 likely benign Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000011486 SCV000543768 other Fabry disease 2018-12-27 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000487818 SCV000575658 benign not provided 2023-04-01 criteria provided, single submitter clinical testing GLA: BP2, BP5, BS3:Supporting, BS1
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000487818 SCV000609890 likely benign not provided 2017-06-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035314 SCV000695753 likely benign not specified 2023-10-13 criteria provided, single submitter clinical testing 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000035314 SCV000740567 likely benign not specified 2016-07-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000487818 SCV000885525 benign not provided 2023-11-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769536 SCV000900931 likely benign Cardiomyopathy 2023-04-19 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000011486 SCV000902838 benign Fabry disease 2018-03-16 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego RCV000346926 SCV000995806 likely benign Hypertrophic cardiomyopathy 2017-07-26 criteria provided, single submitter clinical testing
Mendelics RCV000011486 SCV001141977 likely benign Fabry disease 2019-05-28 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000011486 SCV001440321 benign Fabry disease 2019-01-01 criteria provided, single submitter clinical testing
CeMIA RCV000011486 SCV001571670 uncertain significance Fabry disease criteria provided, single submitter clinical testing 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.
Genome-Nilou Lab RCV000011486 SCV001652719 uncertain significance Fabry disease 2021-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000487818 SCV001898477 benign not provided 2015-03-03 criteria provided, single submitter clinical testing 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)
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital RCV000011486 SCV001984289 benign Fabry disease 2020-07-23 criteria provided, single submitter clinical testing
Cohesion Phenomics RCV000346926 SCV003800594 benign Hypertrophic cardiomyopathy 2022-09-29 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000487818 SCV004235158 uncertain significance not provided 2023-11-10 criteria provided, single submitter clinical testing
OMIM RCV000011486 SCV000031718 uncertain significance Fabry disease 2013-01-01 no assertion criteria provided literature only

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