ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1177C>T (p.Arg393Ter) (rs121907963)

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Total submissions: 5
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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 2018-08-15 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hexosaminidase A deficiency (PMID: 1837283, 21796138, 24518553). ClinVar contains an entry for this variant (Variation ID: 3905). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). 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.
OMIM RCV000004111 SCV000024277 pathogenic 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

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