Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV000516959 | SCV000614283 | pathogenic | not provided | 2020-08-12 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of pathogenic variants identified in NOTCH3 involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain. |
| ARUP Laboratories, |
RCV000516959 | SCV001474558 | likely pathogenic | not provided | 2019-11-07 | criteria provided, single submitter | clinical testing | The NOTCH3 c.3356G>A; p.Cys1119Tyr variant (rs1266914122) is reported in the literature in at least one individual affected with CADASIL (Kim 2014). This variant is reported in ClinVar (Variation ID: 447834), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The cysteine at codon 1119 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). Based on available information, this variant is considered to be likely pathogenic. References: Kim YE et al. Spectrum of NOTCH3 mutations in Korean patients with clinically suspicious cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Neurobiol Aging. 2014 Mar;35(3):726.e1-6. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. |
| Invitae | RCV000516959 | SCV004523860 | uncertain significance | not provided | 2024-01-26 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1119 of the NOTCH3 protein (p.Cys1119Tyr). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical feature of cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 24139282, 31719132, 31915071). ClinVar contains an entry for this variant (Variation ID: 447834). 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%. 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. |