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

gnomAD frequency: 0.00308  dbSNP: rs28935490

Total submissions: 26

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 (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.
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 (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".
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: 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