ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.200G>T (p.Cys67Phe)

dbSNP: rs1555729615
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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 Inc RCV000516950 SCV000614249 pathogenic not provided 2023-08-07 criteria provided, single submitter clinical testing This variant has been identified in at least one individual with clinical features associated with CADASIL. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. 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).
Invitae RCV000516950 SCV002953835 likely pathogenic not provided 2022-10-09 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys67 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been observed in individuals with NOTCH3-related conditions (PMID: 12589106, 19174371), which suggests that this may be a clinically significant amino acid residue. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (CADASIL) (PMID: 31418856; Invitae). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 67 of the NOTCH3 protein (p.Cys67Phe). ClinVar contains an entry for this variant (Variation ID: 447806). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive.

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