ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.496del (p.Arg166fs)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264519 SCV001442713 pathogenic Tay-Sachs disease 2020-10-26 criteria provided, single submitter clinical testing Variant summary: HEXA c.496delC (p.Arg166AlafsX33) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251210 control chromosomes. c.496delC has been reported in the literature in at-least one individual affected with Tay-Sachs Disease and has been subsequently observed within settings of numerous carrier screening programs (example, Drucker_1997, Zlotogara_2019). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of normal enzyme activity in obligate carriers at levels expected for this genotype and further supported by the absence of steady-state levels of mRNA (example, Drucker_1997). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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