ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1549dup (p.Leu517fs) (rs1555472161)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000633126 SCV000754338 uncertain significance Tay-Sachs disease 2018-01-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the HEXA gene (p.Leu517Profs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 13 amino acids of the HEXA protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family affected with Tay-Sachs disease (PMID: 9150157). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000633126 SCV000919502 likely pathogenic Tay-Sachs disease 2018-03-22 criteria provided, single submitter clinical testing Variant summary: HEXA c.1549dupC (p.Leu517ProfsX7) 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. Although this frameshift variant is located 13 amino acids from the end of the protein, it has been reported in first-cousin parents of an infant who died of Tay-Sachs Disease (Akerman_1997). The variant was absent in 246258 control chromosomes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 likely pathogenic.

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