ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.937G>T (p.Asp313Tyr) (rs28935490)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000487818 SCV000885525 likely benign not provided 2018-06-12 criteria provided, single submitter clinical testing The X-linked p.Asp313Tyr variant (rs28935490) has been reported in association with Fabry disease (Eng 1993, Guffon 1998, and du Moulin 2017). Froissart (2003) reported this variant in a symptomatic male patient, who carried a second GLA variant with clear loss of biochemical function. The aforementioned study further reported the p.Asp313Tyr variant in a healthy male. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.4 percent in the European Non-Finnish population (identified on 404 out of 90,624 chromosomes, including 172 hemizygotes and 1 homozygote) and has been reported to the ClinVar database as likely benign (Variation ID: 10738). Functional studies have demonstrated that the p.Asp313Tyr GLA variant retains near wild type enzyme activity with normal cell localization in lysosomes and is likely a pseudodeficient allele of GLA (Yasuda 2003 and Froissart 2003). Altogether the p.Asp313Tyr variant is considered to be likely benign.
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".
Ambry Genetics RCV000250525 SCV000318693 benign Cardiovascular phenotype 2018-01-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Subpopulation frequency in support of benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769536 SCV000900931 likely benign Cardiomyopathy 2017-10-05 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000011486 SCV000212218 likely benign Fabry disease 2015-03-11 criteria provided, single submitter research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487818 SCV000575658 uncertain significance not provided 2017-05-31 criteria provided, single submitter clinical testing
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
Color RCV000011486 SCV000902838 benign Fabry disease 2018-03-16 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000011486 SCV000734724 likely benign Fabry disease no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000487818 SCV000331021 other not provided 2018-08-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000011486 SCV000481400 likely benign Fabry disease 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000346926 SCV000481401 likely benign Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000035314 SCV000695753 uncertain significance not specified 2017-05-16 criteria provided, single submitter clinical testing Variant summary: The GLA c.937G>T (p.Asp313Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide and results in a replacement of a medium size and acidic Aspartate (D) with a large size and aromatic Tyrosine (Y) containing hydroxyl group. 4/4 in silico tools predict damaging outcome for this variant. This variant was found in 279/89622 control chromosomes (one homozygote) including ExAC at a frequency of 0.0031131, which does not exceed the estimated maximal expected allele frequency of a pathogenic GLA variant (0.005). This variant was predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.004396 (211/48000). This observed frequency in general is in similar range that of the estimated maximal expected allele frequency of a pathogenic GLA variant (0.005), suggesting this is possibly a polymorphism found primarily in the populations of European (Non-Finnish) origin. In addition hemizygote rate of this variant in ExAC is 1/260 (129/33644 males) which far exceeds the disease prevalence of Fabry disease (1/50000), supporting benign outcome. In literature, this variant has been observed in large phenotypic range of patients, from clinically normal to classic Fabry disease patients, including cardiological and renal manifestations. Most (but not all) patients have reduced alpha galactosidase-A activity in plasma, but no Fabry disease-specific organ manifestations. 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 (Yasuda et al. 2003). Overall, functional studies suggest that the D313Y variant is a functional polymorphism rather than a disease-causing variant. This variant was found in three male patients with Classical Fabry disease in the same phase (in cis) with other missense variants R112C, G411D and C172G. These latter mutations individually showed impaired enzyme activity and were presumably misfolded and/or unstable, resulting in their retention in the endoplasmic reticulum and subsequent proteosome degradation. The variant of interest was also found in a female patient together with a pathogenic variant c.835C>G (p.Q279E; phase is unknown). In summary, the D313Y causes a pseudodeficiency of the alpha galactosidase-A which does not cause Fabry disease, however it may be associated with the risk of cerebrovascular disease. Therefore, presence of the D313Y mutation in a patient with Fabry disease should prompt further investigation to detect a second causative mutation. In addition, several clinical diagnostic laboratories/reputable databases classified this variant as likely benign while one lab classified it as variant of uncertain significance. Taken together, the variant is classified as a Variant of Unknown Significance-possibly benign.
Invitae RCV000011486 SCV000543768 other Fabry disease 2018-12-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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.
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
OMIM RCV000011486 SCV000031718 uncertain significance Fabry disease 2013-01-01 no assertion criteria provided literature only
PreventionGenetics RCV000035314 SCV000302837 likely benign not specified criteria provided, single submitter clinical testing

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