Submissions for variant NM_000435.3(NOTCH3):c.194G>C (p.Cys65Ser)

dbSNP: rs1555730176

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000517084	SCV000614246	pathogenic	not provided	2024-11-22	criteria provided, single submitter	clinical testing	This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. 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 CADASIL. 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).
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253000	SCV001428498	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2018-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000517084	SCV001474396	likely pathogenic	not provided	2019-07-30	criteria provided, single submitter	clinical testing	The NOTCH3 c.194G>C; p.Cys65Ser variant is reported in the literature in individuals affected with CADASIL (Opherk 2004, Peters 2005). This variant is reported in ClinVar (Variation ID: 447803), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 65 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.193T>G; p.Cys65Gly, c.194G>A; p.Cys65Tyr) have been reported in individuals with CADASIL (Bianchi 2007, Cleves 2010, Lackovic 2012). 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, the p.Cys65Ser variant is considered to be likely pathogenic. References: Bianchi S et al. Novel human pathological mutations. Gene symbol: NOTCH3. Disease: CADASIL, exon 2 mutation. Hum Genet. 2007 Dec;122(5):558-9. Cleves C et al. Genetically confirmed CADASIL in a pediatric patient. Pediatrics. 2010 Dec;126(6):e1603-7. Lackovic V et al. Skin and sural nerve biopsies: ultrastructural findings in the first genetically confirmed cases of CADASIL in Serbia. Ultrastruct Pathol. 2012 Oct;36(5):325-35. Opherk C et al. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004 Nov;127(Pt 11):2533-9. Peters N et al. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. 2005 Jul;62(7):1091-4. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000517084	SCV002193605	pathogenic	not provided	2024-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 65 of the NOTCH3 protein (p.Cys65Ser). 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 (PMID: 15364702, 16009764). ClinVar contains an entry for this variant (Variation ID: 447803). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NOTCH3 protein function with a positive predictive value of 95%. This variant disrupts the p.Cys65 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been observed in individuals with NOTCH3-related conditions (PMID: 21078731, 23025651), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000517084	SCV005413356	pathogenic	not provided	2023-10-23	criteria provided, single submitter	clinical testing	PP2, PP3, PP4, PM1, PM2_moderate, PM5, PS3, PS4