ClinVar Miner

Submissions for variant NM_000521.4(HEXB):c.445+1G>C (rs761197472)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000248071 SCV000304653 benign not specified criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000709991 SCV000810662 pathogenic Sandhoff disease 2018-09-11 criteria provided, single submitter clinical testing
Invitae RCV000709991 SCV000959270 likely pathogenic Sandhoff disease 2019-04-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the HEXB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HEXB-related conditions. ClinVar contains an entry for this variant (Variation ID: 256358). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HEXB are known to be pathogenic (PMID: 7550345, 18758829). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000709991 SCV001572886 pathogenic Sandhoff disease 2021-02-12 criteria provided, single submitter clinical testing A homozygous 3’ splice site variation in intron 2 of the HEXB gene was detected. The observed variant c.445+1G>C has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2. In summary, the variant meets our criteria to be classified as pathogenic.

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