ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1528C>T (p.Arg510Ter) (rs786204585)

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Total submissions: 5
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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
Foundation for Research in Genetics and Endocrinology,Institute of Human Genetics RCV000169328 SCV000494230 pathogenic Tay-Sachs disease 2010-08-26 no assertion criteria provided research
GeneDx RCV000421085 SCV000521178 pathogenic not provided 2016-12-20 criteria provided, single submitter clinical testing The R510X variant in the HEXA gene has been reported multiple times in patients with Tay-Sachs disease and has been associated with infantile-onset Tay-Sachs disease when present in the homozygous state (Kaya et al. 2011; Gort et al. 2012; Sheth et al. 2014). The R510X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R510X variant is predicted to cause loss of normal protein function through protein truncation. In summary, we interpret R510X to be pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000169328 SCV000814792 pathogenic Tay-Sachs disease 2018-03-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the HEXA gene (p.Arg510*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 20 amino acids of the HEXA protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous or in combination with another HEXA variant in several individuals affected with hexosaminidase A deficiency (PMID: 22789865, 27896118, 21567908). 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, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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