Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000518543 | SCV000614222 | pathogenic | not provided | 2021-02-08 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. 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, |
RCV001000977 | SCV001158077 | likely pathogenic | not specified | 2018-12-26 | criteria provided, single submitter | clinical testing | The NOTCH3 c.1364G>A; p.Cys455Tyr variant (rs886041513), is reported in the literature in at least one individual affected with CADASIL (Kim 2014). This variant is reported in ClinVar (Variation ID: 447784), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 455 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This variant lies within an EGF-like repeat domain, and pathogenic variants resulting in the gain or loss of a cysteine residue are common in these repeats and are predicted to disrupt protein structure (Dichgans 2000, Joutel 1997, Rutten 2016). Additionally, another variant at this codon (c.1363C>T, p.Cys455Arg) has been reported in individuals with CADASIL and is considered pathogenic (Arboleda-Velasquez 2002). Based on available information, the p.Cys455Tyr variant is considered to be likely pathogenic. References: Arboleda-Velasquez JF et al. C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke. Neurology. 2002 Jul 23;59(2):277-9. Dichgans M et al. Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet. 2000 Apr;8(4):280-5. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. 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 J et al. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain. 2016 Apr;139(Pt 4):1123-35. |
| Labcorp Genetics |
RCV000518543 | SCV003443134 | uncertain significance | not provided | 2022-10-31 | criteria provided, single submitter | clinical testing | 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. 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: 447784). This missense change has been observed in individual(s) with NOTCH3-related conditions (PMID: 24139282). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 455 of the NOTCH3 protein (p.Cys455Tyr). |
| Mayo Clinic Laboratories, |
RCV000518543 | SCV004225138 | likely pathogenic | not provided | 2022-08-02 | criteria provided, single submitter | clinical testing | PP2, PP3, PM1, PM2, PM5 |