Total submissions: 26
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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, |
RCV000011486 | SCV000212218 | likely benign | Fabry disease | 2015-03-11 | criteria provided, single submitter | research | |
Agnes Ginges Centre for Molecular Cardiology, |
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". |
Prevention |
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 |
RCV000487818 | SCV000331021 | other | not provided | 2018-08-22 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
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, |
RCV000346926 | SCV000481401 | likely benign | Hypertrophic cardiomyopathy | 2016-06-14 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000011486 | SCV000543768 | other | Fabry disease | 2018-12-27 | criteria provided, single submitter | clinical testing | |
Ce |
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, |
RCV000487818 | SCV000609890 | likely benign | not provided | 2017-06-29 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000035314 | SCV000695753 | benign | not specified | 2024-10-14 | 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 0.0038 in 1210097 control chromosomes, predominantly at a frequency of 0.0044 within the Non-Finnish European subpopulation in the gnomAD database (v4), including 5 homozygotes and 1278 hemizygotes. This frequency is slightly lower than estimated for a pathogenic variant in GLA causing Fabry Disease (0.0038 vs 0.005) however the presence of a high number of hemizygotes suggests a generally benign role for the variant. c.937G>T 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. Co-occurrences with other pathogenic variant(s) have been reported (GLA c.1232G>A, p.Gly411Asp; GLA c.334C>T, p.Arg112Cys; GLA c.514T>G, p.Cys172Gly; GLA c.811G>A, p.Gly271Ser; GLA c.835C>G , p.Gln279Glu), providing supporting evidence for a benign role. Functional studies have shown that Asp313Tyr does not disrupt enzyme structure, has >90% residual enzyme activity and is stable at lysosomal pH (4.5) (Yasuda_2003). Overall, functional studies suggest that the Asp313Tyr 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 Asp313Tyr 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). ClinVar contains an entry for this variant (Variation ID: 10738). Based on the evidence outlined above, the variant was classified as benign. |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000035314 | SCV000740567 | likely benign | not specified | 2016-07-29 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000487818 | SCV000885525 | benign | not provided | 2023-11-03 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
RCV000769536 | SCV000900931 | likely benign | Cardiomyopathy | 2023-04-19 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000011486 | SCV000902838 | benign | Fabry disease | 2018-03-16 | criteria provided, single submitter | clinical testing | |
Center for Advanced Laboratory Medicine, |
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, |
RCV000011486 | SCV001440321 | benign | Fabry disease | 2019-01-01 | criteria provided, single submitter | clinical testing | |
Ce |
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- |
RCV000011486 | SCV001652719 | uncertain significance | Fabry disease | 2021-05-18 | criteria provided, single submitter | clinical testing | |
Gene |
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, |
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, |
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 |