ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1528C>T (p.Arg510Ter)

gnomAD frequency: 0.00001  dbSNP: rs786204585
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169328 SCV000220663 likely pathogenic Tay-Sachs disease 2014-09-02 criteria provided, single submitter literature only
GeneDx RCV000421085 SCV000521178 pathogenic not provided 2022-06-06 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 20 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27896118, 21567908, 22789865, 33547378)
Invitae RCV000169328 SCV000814792 pathogenic Tay-Sachs disease 2021-11-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg510*) in the HEXA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 20 amino acid(s) of the HEXA protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hexosaminidase A deficiency (PMID: 21567908, 22789865, 27896118). ClinVar contains an entry for this variant (Variation ID: 188954). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169328 SCV000919503 pathogenic Tay-Sachs disease 2018-04-02 criteria provided, single submitter clinical testing Variant summary: HEXA c.1528C>T (p.Arg510X) 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 was absent in 120496 control chromosomes (ExAC and publication controls). The variant, c.1528C>T, has been reported in the literature in multiple individuals affected with Tay-Sachs Disease. 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%-<30% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000169328 SCV002030166 pathogenic Tay-Sachs disease 2021-09-28 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Myriad Women's Health, Inc. RCV000169328 SCV002060198 pathogenic Tay-Sachs disease 2021-11-10 criteria provided, single submitter clinical testing NM_000520.4(HEXA):c.1528C>T(R510*) is a nonsense variant classified as pathogenic in the context of hexosaminidase A deficiency. R510* has been observed in cases with relevant disease (PMID: 33547378, 27896118, 21567908). Functional assessments of this variant are not available in the literature. R510* has not been observed in population frequency databases. In summary, NM_000520.4(HEXA):c.1528C>T(R510*) is a nonsense variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and 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 RCV000169328 SCV000494230 pathogenic Tay-Sachs disease 2010-08-26 no assertion criteria provided research
PerkinElmer Genomics RCV000169328 SCV002024981 pathogenic Tay-Sachs disease 2020-10-20 no assertion criteria provided clinical testing
Natera, Inc. RCV000169328 SCV002085648 pathogenic Tay-Sachs disease 2017-12-09 no assertion criteria provided clinical testing

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