ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1177C>T (p.Arg393Ter)

gnomAD frequency: 0.00001  dbSNP: rs121907963
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522695 SCV000617693 pathogenic not provided 2017-10-20 criteria provided, single submitter clinical testing The R393X variant in the HEXA gene has been reported previously in association with infantile Tay-Sachs disease (Akli et al., 1991; Ozkara et al., 1998; Haghighi et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R393X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R393X as a pathogenic variant.
Invitae RCV000004111 SCV000955425 pathogenic Tay-Sachs disease 2023-11-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg393*) in the HEXA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is present in population databases (rs121907963, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hexosaminidase A deficiency (PMID: 1837283, 21796138, 24518553, 32968423). ClinVar contains an entry for this variant (Variation ID: 3905). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000004111 SCV001482257 pathogenic Tay-Sachs disease 2021-02-22 criteria provided, single submitter clinical testing Variant summary: HEXA c.1177C>T (p.Arg393X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251470 control chromosomes (gnomAD). c.1177C>T has been reported in the literature in multiple individuals (including several homozygous patients) affected with Tay-Sachs Disease (example: Akli_1991, Jamali_2014, Naseer_2020). These data indicate that the variant is very likely to be associated with disease. Akli et al report that northern blot analysis of fibroblasts derived from a patient homozygous for the variant showed no detectable level of mRNA (Akli_1991). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000004111 SCV002024985 pathogenic Tay-Sachs disease 2019-02-13 criteria provided, single submitter clinical testing
OMIM RCV000004111 SCV000024277 affects Tay-Sachs disease 1991-09-01 no assertion criteria provided literature only
Counsyl RCV000004111 SCV001132224 likely pathogenic Tay-Sachs disease 2015-04-22 no assertion criteria provided clinical testing
Natera, Inc. RCV000004111 SCV002085677 pathogenic Tay-Sachs disease 2017-03-17 no assertion criteria provided clinical testing

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