ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.316T>C (p.Cys106Arg)

dbSNP: rs1555729589
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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 RCV000518402 SCV000614276 pathogenic not provided 2016-10-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000518402 SCV003443137 pathogenic not provided 2022-06-24 criteria provided, single submitter clinical testing This missense change has been observed in individuals with autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PMID: 32277177; Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys106 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been observed in individuals with NOTCH3-related conditions (PMID: 15364702, 25973016, 32277177), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 447828). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 106 of the NOTCH3 protein (p.Cys106Arg).

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