Submissions for variant NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)

gnomAD frequency: 0.00001  dbSNP: rs775267348

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000517748	SCV000614321	pathogenic	not provided	2023-03-24	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with CADASIL. In some published literature, this variant is referred to as c.697C>T. 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).
GeneDx	RCV000517748	SCV000617300	likely pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27890607, 31589614, 36535904, 35822697, 34297860, 31433517, 36401683, Moroz2018[CaseReport], 20935329, 16009764, 11102981, 15834039, 32277177, Dogan2023[casereport], 24844136)
Fulgent Genetics, Fulgent Genetics	RCV000763039	SCV000893516	likely pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1; Lateral meningocele syndrome; Myofibromatosis, infantile, 2	2018-10-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000517748	SCV001158574	likely pathogenic	not provided	2020-03-05	criteria provided, single submitter	clinical testing	The NOTCH3 c.619C>T; p.Arg207Cys variant (rs775267348) is reported in the literature in multiple individuals and families affected with CADASIL (Dotti 2005, Escary 2000, Matsushima 2017, Oberstein 1999, Singhal 2004). This variant is found on only two chromosomes (2/250308 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic/likely pathogenic by several laboratories in ClinVar (Variation ID: 447862). The arginine at codon 207 is moderately conserved and occurs in the fifth EGF-like domain, although computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. 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.Arg207Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Dotti MT et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry. 2005 May;76(5):736-8. Escary JL et al. Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. Hum Mutat. 2000 Dec;16(6):518-26. Matsushima T et al. Genotype-phenotype correlations of cysteine replacement in CADASIL. Neurobiol Aging. 2017 Feb;50:169.e7-169.e14. Oberstein SA et al. Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. Neurology. 1999 Jun 10;52(9):1913-5. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Singhal S et al. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004 Sep;127(Pt 9):2031-8.
CeGaT Center for Human Genetics Tuebingen	RCV000517748	SCV001249853	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000517748	SCV002225150	pathogenic	not provided	2024-01-31	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 207 of the NOTCH3 protein (p.Arg207Cys). This variant is present in population databases (rs775267348, gnomAD 0.002%). This missense change has been observed in individuals with CADASIL (PMID: 15834039, 16009764, 20935329, 27890607). ClinVar contains an entry for this variant (Variation ID: 447862). 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.
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV003330087	SCV004037373	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2019-07-17	criteria provided, single submitter	clinical testing	The R207C variant in the NOTCH3 gene is a heterozygous missense variant, which results in the substitution of an arginine residue at the 207 position to cysteine. This variant localizes to coding exon 4 of the NOTCH3 gene (33 coding exons in total; NP_000426.2) and is part of the EGF-like 5 domain. In silico analyses are inconsistent in predicting the effect of this variant on protein structure and/ or function: it is predicted to be deleterious and damaging to protein structure and/ or function by PROVEAN but predicted to be tolerated by SIFT. This variant is present in the Genome Aggregation Database (gnomAD) at a very low frequency (2/250,308), indicating it is not a common benign variant in the populations represented in these databases. Mutations in NOTCH3 are associated with Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (CADASIL) (OMIM#125310). This specific variant has been described to be disease causing in several cohorts of individuals with CADASIL (PMIDs: 27890607, 26305465, 25623805, 15834039, 10371548, 22664156), and is reported in the ClinVar database as Pathogenic/Likely Pathogenic (Variation ID: 447862).
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003330087	SCV004809440	uncertain significance	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2024-04-04	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV001374652	SCV001571575	likely pathogenic	Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy	2020-11-19	no assertion criteria provided	clinical testing