Submissions for variant NM_000435.3(NOTCH3):c.457C>T (p.Arg153Cys)

dbSNP: rs797045014

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626690	SCV000747393	pathogenic	Ischemic stroke; Transient ischemic attack	2017-01-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001554929	SCV001160061	pathogenic	not provided	2022-05-02	criteria provided, single submitter	clinical testing	The NOTCH3 c.457C>T; p.Arg153Cys variant (rs797045014) is reported in the literature in multiple individuals affected with CADASIL (Ceroni 2000, Joutel 1997, Konialis 2007, Mandellos 2005, Matsushima 2017, Tarzjani 2018). This variant is reported as pathogenic in ClinVar (Variation ID: 208501), 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 arginine at codon 153 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This variant lies with 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 2007, Rutten 2016). Based on available information, the p.Arg153Cys variant is considered to be pathogenic. References: Ceroni M et al. Migraine with aura and white matter abnormalities: Notch3 mutation. Neurology. 2000 May 9;54(9):1869-71. 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. Konialis C et al. Pregnancy following preimplantation genetic diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Prenat Diagn. 2007 Nov;27(11):1079-83. Mandellos D et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a Greek family. Neurol Sci. 2005 Oct;26(4):278-81. Matsushima T et al. Genotype-phenotype correlations of cysteine replacement in CADASIL. Neurobiol Aging. 2017 Feb;50:169.e7-169.e14. Rutten JW et al. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain. 2016 Apr;139(Pt 4):1123-35. Tarzjani SPC et al. Genetic study of the NOTCH3 gene in CADASIL patients. Egypt J Med Hum Genet. 2018 Oct;19(4):425-7.
GeneDx	RCV001554929	SCV001776265	likely pathogenic	not provided	2020-06-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32277177, 31915071, 31680059, 32470649, 30956055, 31584664, 17729386, 10802804, 27890607, 9388399, 16193256)
Athena Diagnostics	RCV001554929	SCV001879616	pathogenic	not provided	2022-12-12	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features of CADASIL. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: 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 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).
CeGaT Center for Human Genetics Tuebingen	RCV001554929	SCV001961792	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
DASA	RCV000190514	SCV002061150	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.457C>T;p.(Arg153Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar: 208501; PMID: 27206574; 28710804; 31915071; 32457593) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (EGF) - PM1. This variant is not present in population databases (rs797045014, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in NOTCH3 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Invitae	RCV001554929	SCV003443892	pathogenic	not provided	2024-01-17	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 153 of the NOTCH3 protein (p.Arg153Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CADASIL (PMID: 9388399, 10802804, 16193256, 27890607). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208501). 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.
Mendelics	RCV000190514	SCV000245400	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2014-04-22	no assertion criteria provided	clinical testing