ClinVar Miner

Submissions for variant NM_000521.4(HEXB):c.1243-2A>G

gnomAD frequency: 0.00001  dbSNP: rs398123446
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000079057 SCV000225232 pathogenic not provided 2012-08-29 criteria provided, single submitter clinical testing
GeneDx RCV000079057 SCV000490555 pathogenic not provided 2019-07-30 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016)
Counsyl RCV000174010 SCV000795184 likely pathogenic Sandhoff disease 2017-10-31 criteria provided, single submitter clinical testing
Invitae RCV000174010 SCV001574428 pathogenic Sandhoff disease 2023-08-30 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10 of the HEXB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs398123446, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with Sandhoff disease (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 93197). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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