ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1123del (p.Glu375fs) (rs766138785)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169594 SCV000221104 likely pathogenic Tay-Sachs disease 2015-01-30 criteria provided, single submitter literature only
Invitae RCV000169594 SCV001204958 pathogenic Tay-Sachs disease 2019-02-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu375Argfs*7) in the HEXA gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual affected with Tay-Sachs disease (PMID: 16088929). ClinVar contains an entry for this variant (Variation ID: 189166). 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.
Integrated Genetics/Laboratory Corporation of America RCV000169594 SCV001362846 pathogenic Tay-Sachs disease 2019-11-25 criteria provided, single submitter clinical testing Variant summary: HEXA c.1123delG (p.Glu375ArgfsX7) 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 allele was found at a frequency of 8.1e-06 in 246288 control chromosomes. c.1123delG has been reported in the literature in individuals affected with Tay-Sachs Disease (example, Montalvo_2005, Jamrozik_2013, Jahnova_2019). These data indicate that the variant is likely to be associated with disease. No experimental evidence demonstrating an impact on protein function were ascertained in the context of this evaluation. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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