ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.2984del (p.Pro995fs)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV004997597 SCV005621395 uncertain significance not provided 2023-12-21 criteria provided, single submitter clinical testing Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) This variant is predicted to result in a premature termination codon and the loss of a functional protein. However, research supports that pathogenic variants causing CADASIL do so by a toxic gain of function mechanism and the clinical relevance of loss of function (LOF) variants in this gene is under debate in the literature (PMID: 24000151, 25260852, 25870235). Internal data suggests that loss of function variants are more likely pathogenic than benign, but further studies are needed to understand their effect on NOTCH3 signaling. Greater than 90% of NOTCH3 pathogenic variants associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673).

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