Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV000710995 | SCV000841311 | pathogenic | not provided | 2018-07-10 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV000710995 | SCV001471018 | likely pathogenic | not provided | 2019-11-26 | criteria provided, single submitter | clinical testing | The NOTCH3 c.1816T>C; p.Cys606Arg variant (rs1568359346) has been described in association with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; Testi 2012). It is reported as pathogenic in ClinVar (Variation ID: 585598), and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 606 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this position (c.1817G>T; p.Cys606Phe) has been described in an individual with CADASIL (Chen 2017). Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014), and thus the p.Cys606Arg variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. REFERENCES Chen S et al. Clinical features and mutation spectrum in Chinese patients with CADASIL: A multicenter retrospective study. CNS Neurosci Ther. 2017 Sep;23(9):707-716. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Testi S et al. Mutational and haplotype map of NOTCH3 in a cohort of Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). J Neurol Sci. 2012 Aug 15;319(1-2):37-41. |
| Invitae | RCV000710995 | SCV002301672 | pathogenic | not provided | 2023-03-19 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 606 of the NOTCH3 protein (p.Cys606Arg). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys606 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been observed in individuals with NOTCH3-related conditions (PMID: 28710804), 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: 585598). This missense change has been observed in individuals with clinical features of autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 22664156; Invitae). This variant is not present in population databases (gnomAD no frequency). |