ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1422G>C (p.Trp474Cys)

gnomAD frequency: 0.00001  dbSNP: rs121907981
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001244261 SCV001417469 pathogenic Tay-Sachs disease 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 474 of the HEXA protein (p.Trp474Cys). This variant is present in population databases (rs121907981, gnomAD 0.003%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 9603435). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3941). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HEXA function (PMID: 9603435). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity Omics RCV001244261 SCV002023463 likely pathogenic Tay-Sachs disease 2019-12-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001244261 SCV002041572 pathogenic Tay-Sachs disease 2021-11-28 criteria provided, single submitter clinical testing Variant summary: HEXA c.1422G>C (p.Trp474Cys) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of 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 1.2e-05 in 251254 control chromosomes. c.1422G>C has been reported in the literature as a compound heterozygous genotype in at-least two affected sibling individuals with Tay-Sachs Disease who have been subsequently cited by others and included in clinical trials (example, Petroulakis_1998, Neudorfer_2005, Clarke_2011). These data indicate that the variant is likely to be associated with disease. At least one publication reports variant specific experimental evidence evaluating an impact on protein function (Petroulakis_1998). The most pronounced variant effect results in <10% of normal enzyme activity measured as expressed levels of alpha-subunit activity in COS-7 cells. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000004147 SCV000024313 pathogenic Gm2-gangliosidosis, subacute 1998-01-01 no assertion criteria provided literature only

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