Submissions for variant NM_000435.3(NOTCH3):c.1279C>T (p.Arg427Cys)

dbSNP: rs1599391536

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV000999638	SCV001428752	likely pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2019-11-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811559	SCV002048391	likely pathogenic	not provided	2020-12-04	criteria provided, single submitter	clinical testing	The NOTCH3 c.1279C>T; p.Arg427Cys variant (rs1599391536) is reported in the literature in four individuals affected with CADASIL (Dziewulska 2018, Hewamadduma 2010, Liao 2015). This variant is reported as likely pathogenic in ClinVar (Variation ID: 810779). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 427 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.877). 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.Arg427Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Dziewulska D et al. Nuclear abnormalities in vascular myocytes in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neuropathology. 2018 Dec;38(6):601-608. Hewamadduma C et al. POG09 CADASIL in a mother and son due to a novel mutation of the NOTCH-3 gene. Journal of Neurology, Neurosurgery & Psychiatry 2010;81:e50. Liao YC et al. Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles. PLoS One. 2015;10(8):e0136501. Published 2015 Aug 26. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603.
Athena Diagnostics	RCV001811559	SCV002771715	pathogenic	not provided	2021-06-29	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 multiple unrelated individuals with clinical features associated with NOTCH3 involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001811559	SCV003443275	pathogenic	not provided	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 427 of the NOTCH3 protein (p.Arg427Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of CADASIL (PMID: 26618768, 30402942, 32387185). ClinVar contains an entry for this variant (Variation ID: 810779). 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%. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000999638	SCV004812454	likely pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2023-06-06	criteria provided, single submitter	clinical testing	This sequence change in NOTCH3 is predicted to replace arginine with cysteine at codon 427, p.(Arg427Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and introduces an odd number of cysteine residues in EGF-like repeat domain 10 expected to disrupt the disulphide bonds in this domain leading to protein aggregation (PMID: 20301673). There is a large physicochemical difference between arginine and cysteine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in at least six individuals with a clinical diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), (PMID: 30402942, 20167921, 34851492, 32387185, 26308724). At least one of these individuals had a positive skin biopsy for granular osmiophillic material, specific for CADASIL (PMID: 26618768). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.877). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4, PM1, PM2_Supporting, PP3, PP4.
GenomeConnect - CureCADASIL	RCV000999638	SCV001156357	not provided	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 06-13-2016 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.