Submissions for variant NM_000435.3(NOTCH3):c.194G>A (p.Cys65Tyr)

dbSNP: rs1555730176

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001942733	SCV002128714	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. This variant disrupts the p.Cys65 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15364702, 16009764, 21078731). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1365706). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 65 of the NOTCH3 protein (p.Cys65Tyr). 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 (CADASIL) (PMID: 23025651; Invitae).
Athena Diagnostics	RCV001942733	SCV002771722	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	This variant has been identified in at least one individual with clinical features of 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 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, Molecular Genetics and Genomics, ARUP Laboratories	RCV001942733	SCV005876497	likely pathogenic	not provided	2024-02-19	criteria provided, single submitter	clinical testing	The NOTCH3 c.194G>A; p.Cys65Tyr variant (rs1555730176) is reported in the literature in several individuals affected with CADASIL (Kim 2020, Lackovic 2012, Mukai 2020, Rufa 2007). This variant is reported in ClinVar (Variation ID: 1365706). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.876). Additionally, another variant at this codon (c.194G>C; p.Cys65Ser) has been reported in individuals with CADASIL (Mukai 2020, Opherk 2004). 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.Cys65Tyr variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Kim H et al. Clinical and imaging features of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and cysteine-sparing NOTCH3 mutations. PLoS One. 2020 Jun 18;15(6):e0234797. PMID: 32555735. 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. PMID: 23025651. Mukai M et al. Genotype-phenotype correlations and effect of mutation location in Japanese CADASIL patients. J Hum Genet. 2020 Aug;65(8):637-646. PMID: 32277177. 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. PMID: 15364702. Rufa A et al. Cardiac autonomic nervous system and risk of arrhythmias in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Stroke. 2007 Feb;38(2):276-80. PMID: 17218610. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. PMID: 24844136.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002291003	SCV005883837	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2024-12-03	criteria provided, single submitter	clinical testing	Variant summary: NOTCH3 c.194G>A (p.Cys65Tyr) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 243168 control chromosomes. c.194G>A has been reported in the literature in individuals affected with Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25344745, 35641310, 32277177). ClinVar contains an entry for this variant (Variation ID: 1365706). Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV002291003	SCV002583396	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2022-02-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004536389	SCV004737315	pathogenic	NOTCH3-related disorder	2024-02-07	no assertion criteria provided	clinical testing	The NOTCH3 c.194G>A variant is predicted to result in the amino acid substitution p.Cys65Tyr. This variant was reported in individuals with CADASIL (Lackovic et al. 2012. PubMed ID: 23025651; Mukai et al. 2020. PubMed ID: 32277177). This variant has not been reported in a large population database, indicating this variant is rare. Most CADASIL causing variants in the NOTCH3 gene result in the gain or loss of one or more cysteine residues in the extracellular domain of the protein, as seen in this patient. This patient’s variant alters a cysteine residue and is located in the extracellular EGF-like domain one. Pathogenic variants in EGF-like domains 1-6 appear to be fully penetrant and are usually associated with the classical CADASIL phenotype; however, there is variability in disease severity (OMIM #125310; Rutten et al. 2016. PubMed ID: 27844030; Rutten et al. 2019. PubMed ID: 30032161). This variant is interpreted as pathogenic.