Submissions for variant NM_000435.3(NOTCH3):c.544C>T (p.Arg182Cys)

gnomAD frequency: 0.00001  dbSNP: rs28933697

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000517955	SCV000614313	pathogenic	not provided	2022-12-01	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 of CADASIL, including at least one confirmed de novo. 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).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000517955	SCV001160168	pathogenic	not provided	2023-09-04	criteria provided, single submitter	clinical testing	The NOTCH3 c.544C>T; p.Arg182Cys variant (rs28933697), is reported in the literature in multiple individuals affected with CADASIL (Joutel 1997, Joutel 2000, Oberstein 1999). This variant is reported as pathogenic in ClinVar (Variation ID: 9220), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 182 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.789). 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 1997, Rutten 2016). Based on available information, the p.Arg182Cys variant is considered to be pathogenic. References: 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. Joutel A et al. De novo mutation in the Notch3 gene causing CADASIL. Ann Neurol. 2000 Mar;47(3):388-91. 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. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain. 2016 Apr;139(Pt 4):1123-35.
CeGaT Center for Human Genetics Tuebingen	RCV000517955	SCV001249854	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	NOTCH3: PM1:Strong, PM2, PS4:Moderate, PP2, PP4, PS3:Supporting
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000517955	SCV001446573	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000517955	SCV001776645	pathogenic	not provided	2022-07-12	criteria provided, single submitter	clinical testing	Observed in multiple unrelated patients with clinical features of CADASIL referred for genetic testing at GeneDx and in published literature (Joutel et al., 2000; Dichgans et al., 2000; Escary et al., 2000; Joutel et al., 2001; Singhal et al., 2004; Opherk et al., 2004; Peters et al., 2005; Wang et al., 2011; Chen et al., 2017; Mizuta et al., 2017; Paraskevas et al., 2018); Published functional studies demonstrate recapitulation of CADASIL phenotypes in a transgenic mouse model (Rutten et al., 2015); 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: 27781952, 14618173, 11755616, 15364702, 34335700, 17323840, 8878478, 28717674, 16796587, 29706439, 9388399, 16009764, 10371548, 27350778, 15229130, 11102981, 12810003, 20935329, 26856460, 28710804, 28991717, 33942994, 32277177, 24844136, 10854111, 10716263, 26715087)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000009801	SCV001950078	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2021-08-11	criteria provided, single submitter	clinical testing
Invitae	RCV000517955	SCV002233185	pathogenic	not provided	2023-11-25	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 182 of the NOTCH3 protein (p.Arg182Cys). This variant is present in population databases (rs28933697, gnomAD 0.007%). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (PMID: 12395806, 16009764). ClinVar contains an entry for this variant (Variation ID: 9220). 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.
MGZ Medical Genetics Center	RCV000009801	SCV002581807	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2022-08-12	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000009801	SCV004175686	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2022-11-04	criteria provided, single submitter	clinical testing	The NOTCH3 c.544C>T variant is classified as PATHOGENIC (PS4, PM2_Supporting, PS2_supporting, PM1_Strong, PP3_moderate) The NOTCH3 c.544C>T variant is a single nucleotide change in exon 4/33 of the NOTCH3 gene, which is predicted to change the amino acid arginine at position 182 in the protein to cysteine. The variant has been reported in multiple individuals with a clinical presentation of CADASIL (PMID: 9388399, 15364702) (PS4) and is rare in population databases (PM2-supp). This variant has been reported in one affected patient with no family history of this condition (PMID:10716263) (PS2_supporting). This variant is located in the EGF-like 4 domain and results in a gain of a cysteine residue (PM1-strong). Computational predictions moderately support a deleterious effect on the gene or gene product (PP3_moderate). This variant is in dbSNP (rs28933697), has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID:9220) and has been reported as disease-causing in HGMD (CM961044). This variant has been listed 8 times on the NOTCH3 LOVD
OMIM	RCV000009801	SCV000030022	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2000-03-01	no assertion criteria provided	literature only
GenomeConnect - CureCADASIL	RCV000009801	SCV001156358	not provided	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported, most recently, on 05-09-2018 by lab or GTR ID Athena Diagnostics. 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. Phenotypic details are available under supporting information.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000517955	SCV002035620	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000517955	SCV002037509	pathogenic	not provided		no assertion criteria provided	clinical testing