ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1957C>A (p.Leu653Ile)

dbSNP: rs1336688514
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV001288882 SCV001476279 uncertain significance not provided 2023-11-07 criteria provided, single submitter clinical testing Available data are insufficient to determine the clinical significance of the variant at this time. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been seen where an alternate explanation for disease was also identified, suggesting this variant may not cause disease. Computational tools disagree on the variant's effect on normal protein function. 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).
Labcorp Genetics (formerly Invitae), Labcorp RCV001288882 SCV002301071 uncertain significance not provided 2020-12-20 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NOTCH3 protein function. This variant has not been reported in the literature in individuals with NOTCH3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with isoleucine at codon 653 of the NOTCH3 protein (p.Leu653Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine.

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