ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.754C>T (p.Arg252Cys)

gnomAD frequency: 0.00001  dbSNP: rs566580738
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000625807 SCV000746363 likely pathogenic Tay-Sachs disease 2017-12-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp 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, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences RCV000625807 SCV001244662 likely pathogenic Tay-Sachs disease 2019-07-05 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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, Revvity RCV000625807 SCV002023464 likely pathogenic Tay-Sachs disease 2020-03-02 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. 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, FRIGE's Institute of Human Genetics 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-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, RCV000625807 SCV001244952 uncertain significance Tay-Sachs disease no assertion criteria provided clinical testing
Natera, Inc. RCV000625807 SCV001461555 likely pathogenic Tay-Sachs disease 2020-09-16 no assertion criteria provided clinical testing

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