ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.619T>C (p.Tyr207His) (rs372416832)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000418558 SCV000202801 uncertain significance not provided 2016-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000418558 SCV000535713 likely pathogenic not provided 2017-01-18 criteria provided, single submitter clinical testing The Y207H variant in the GLA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, other missense alterations affecting this residue (Y207S and Y207C) have been reported in association with classic Fabry disease (Shabbeer et al., 2002; Benjamin et al., 2009); in vitro assays demonstrated that the Y207S and Y207C variants significantly diminish alpha-galactosidase-A enzyme activity as compared to the wild-type allele (Wu et al., 2011; Benjamin et al., 2009). Additionally, missense variants in nearby residues (C202YW, W204C, P205T, P205L, P205R, P210S, P210L) have been reported in the Human Gene Mutation Database in association with Fabry disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. The Y207H variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y207H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the information available, the Y207H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000798173 SCV000937774 uncertain significance Fabry disease 2020-10-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 207 of the GLA protein (p.Tyr207His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs372416832, ExAC 0.05%). This variant has not been reported in the literature in individuals with GLA-related disease. ClinVar contains an entry for this variant (Variation ID: 167141). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Tyr207 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 21598360, 19387866), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000798173 SCV001352080 uncertain significance Fabry disease 2020-01-29 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000798173 SCV001422643 uncertain significance Fabry disease 2020-01-22 no assertion criteria provided curation The p.Tyr207His variant in GLA has not been previously reported individuals with Fabr disease but has been identified in 0.05% (6/12013) of African chromosomes, including 4 hemizygotes, by the Genome Aggregation Database (gnomAD, This variant has also been reported in ClinVar (ID: 167141) as likely pathogenic by GeneDx and as a VUS by EGL Genetic Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Tyr207His have been reported in association with disease in ClinVar and the literature, and the variant is located in a region of GLA that forms the active site of the enzyme, suggesting that this variant is in a mutational hotspot and functional domain and supports pathogenicity (PMID: 27560961, 19287194; Variation ID: 585078, 197113). In summary, the clinical significance of the p.Tyr207His variant is uncertain. ACMG/AMP Criteria applied: BS1, PM1, PP3, PM5_Supporting (Richards 2015).

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