Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genomic Research Center, |
RCV000625807 | SCV000746363 | likely pathogenic | Tay-Sachs disease | 2017-12-03 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000625807 | SCV000833988 | pathogenic | Tay-Sachs disease | 2023-10-30 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 252 of the HEXA protein (p.Arg252Cys). This variant is present in population databases (rs566580738, gnomAD 0.006%). This missense change has been observed in individual(s) with HEXA-related diseases (PMID: 31076878; Invitae). ClinVar contains an entry for this variant (Variation ID: 522667). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HEXA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg252 amino acid residue in HEXA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8730294). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Cardiogenetic Research Center, |
RCV000625807 | SCV001244662 | likely pathogenic | Tay-Sachs disease | 2019-07-05 | criteria provided, single submitter | research | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000625807 | SCV001983502 | pathogenic | Tay-Sachs disease | 2021-09-29 | criteria provided, single submitter | clinical testing | Variant summary: HEXA c.754C>T (p.Arg252Cys) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Other missense variant affecting this residue, such as p.Arg252His and p.Arg252Leu have been reported in patients with Tay-Sachs disease, supporting a critical role for this residue for overall function. 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 1.2e-05 in 251466 control chromosomes. c.754C>T has been reported in the literature as a homozygous and compound heterozygous genotype in multiple individuals affected with Tay-Sachs Disease (example, Mistri_2019, Jahnova_2019, King_2020, Mahdieh_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal HEX-A activity with MUGS as a substrate (example, Mistri_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic, n=4, VUS, n=1). None of these submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. |
Revvity Omics, |
RCV000625807 | SCV002023464 | likely pathogenic | Tay-Sachs disease | 2020-03-02 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV000625807 | SCV002060175 | likely pathogenic | Tay-Sachs disease | 2021-11-01 | criteria provided, single submitter | clinical testing | NM_000520.4(HEXA):c.754C>T(R252C) is a missense variant classified as likely pathogenic in the context of hexosaminidase A deficiency. R252C has been observed in cases with relevant disease (PMID: 31076878, 31388111, 33240792). Functional assessments of this variant are not available in the literature. R252C has been observed in population frequency databases (gnomAD: SAS 0.01%). In summary, NM_000520.4(HEXA):c.754C>T(R252C) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. |
Foundation for Research in Genetics and Endocrinology, |
RCV000625807 | SCV002583285 | likely pathogenic | Tay-Sachs disease | 2022-09-30 | criteria provided, single submitter | clinical testing | The variant has shown a homozygous status for c.754C>T (p.Arg252Cys) in exon 7 of the HEXA gene. This variant is not reported in the 1000 genomes and has MAF of 0.0019% in the gnomAD database. It is reported in dbSNP database with ID of rs566580738. The in-silico prediction of the variant is disease causing by LRT, MutPred, Mutation Taster, SIFT and PROVEAN. |
Myelin Disorders Clinic- |
RCV000625807 | SCV001244952 | uncertain significance | Tay-Sachs disease | no assertion criteria provided | clinical testing | ||
Natera, |
RCV000625807 | SCV001461555 | likely pathogenic | Tay-Sachs disease | 2020-09-16 | no assertion criteria provided | clinical testing |