ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1261C>T (p.Arg421Cys)

dbSNP: rs1555729068
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000518409 SCV000614216 pathogenic not provided 2020-03-19 criteria provided, single submitter clinical testing The variant disrupts a cysteine residue in an EGF-like repeat domain, which is important for the structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000518409 SCV001446484 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000518409 SCV002286836 pathogenic not provided 2023-11-15 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 421 of the NOTCH3 protein (p.Arg421Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PMID: 16009764; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 447779). 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 expected to disrupt NOTCH3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

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