rs28935490
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000169.3(GLA):c.937G>T(p.Asp313Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,207,947 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,531 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars).
Frequency
Consequence
NM_000169.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00314 AC: 350AN: 111314Hom.: 1 Cov.: 23 AF XY: 0.00310 AC XY: 104AN XY: 33516
GnomAD3 exomes AF: 0.00303 AC: 556AN: 183499Hom.: 2 AF XY: 0.00352 AC XY: 239AN XY: 67935
GnomAD4 exome AF: 0.00384 AC: 4215AN: 1096579Hom.: 9 Cov.: 30 AF XY: 0.00394 AC XY: 1427AN XY: 361981
GnomAD4 genome AF: 0.00314 AC: 350AN: 111368Hom.: 1 Cov.: 23 AF XY: 0.00310 AC XY: 104AN XY: 33580
ClinVar
Submissions by phenotype
Fabry disease Uncertain:3Benign:6Other:1
Uncertain significance, no assertion criteria provided | literature only | OMIM | Jan 01, 2013 | - - |
other, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 27, 2018 | - pseudodeficiency allele |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Jul 23, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeMIA | - | 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. - |
Benign, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Likely benign, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Mar 11, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2018 | - - |
not provided Uncertain:1Benign:4Other:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | GLA: BP2, BP5, BS3:Supporting, BS1 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | 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) - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 29, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 10, 2023 | - - |
other, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 22, 2018 | - Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles). |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 12, 2024 | - - |
not specified Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 02, 2012 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jul 29, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 14, 2024 | 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. - |
Hypertrophic cardiomyopathy Benign:3
Benign, criteria provided, single submitter | clinical testing | Cohesion Phenomics | Sep 29, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Jul 26, 2017 | - - |
Sudden unexplained death Benign:1
Likely benign, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Mar 27, 2015 | 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". - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 19, 2023 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 11, 2018 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at