ClinVar Miner

Submissions for variant NM_000521.4(HEXB):c.146C>A (p.Ser49Ter)

gnomAD frequency: 0.00001  dbSNP: rs1554034452
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671547 SCV000796532 likely pathogenic Sandhoff disease 2017-12-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000671547 SCV001363963 pathogenic Sandhoff disease 2019-01-10 criteria provided, single submitter clinical testing Variant summary: HEXB c.146C>A (p.Ser49X) 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. A truncation downstream of this position has been classified as pathogenic by our laboratory (eg. c.850C>T (p.Arg284X)). The variant was absent in 204176 control chromosomes (gnomAD). c.146C>A has been reported in the literature in one homozygous individual affected with Sandhoff Disease while, experimental evidence evaluating an impact on protein function demostrated a residual enzymatic activity of 1.6% compared to normal control (Zampieri_2012). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000671547 SCV001579759 pathogenic Sandhoff disease 2020-04-26 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in HEXB are known to be pathogenic (PMID: 7550345, 18758829). This variant has been observed in individual(s) with Sandhoff disease (PMID: 22848519). ClinVar contains an entry for this variant (Variation ID: 555683). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser49*) in the HEXB gene. It is expected to result in an absent or disrupted protein product.

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