Submissions for variant NM_000435.3(NOTCH3):c.328C>T (p.Arg110Cys)

dbSNP: rs775836288

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516674	SCV000614280	pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing	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 occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. This variant appears to segregate with disease in at least one family with CADASIL. 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).
Mendelics	RCV000990179	SCV001141029	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000516674	SCV001160060	pathogenic	not provided	2020-01-13	criteria provided, single submitter	clinical testing	The NOTCH3 c.328C>T; p.Arg110Cys variant is reported in the literature in multiple individuals and families affected with CADASIL (Dichgans 2000, Hung 2018, Joutel 1997, Khan 2016, Opherk 2004, Peters 2005, Singhal 2004, Uyguner 2006, Wang 2011). This variant is reported in ClinVar (Variation ID: 447831), 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 110 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. However, 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). Based on available information, the p.Arg110Cys 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. Hung LY et al. Genetic diagnosis of CADASIL in three Hong Kong Chinese patients: A novel mutation within the intracellular domain of NOTCH3. J Clin Neurosci. 2018 Oct;56:95-100. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Khan MT et al. Successful Use of Intravenous Tissue Plasminogen Activator as Treatment for a Patient with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Case Report and Review of Literature. J Stroke Cerebrovasc Dis. 2016 Apr;25(4):e53-7. 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. Peters N et al. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. 2005 Jul;62(7):1091-4. Singhal S et al. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004 Sep;127(Pt 9):2031-8. Uyguner ZO et al. The R110C mutation in Notch3 causes variable clinical features in two Turkish families with CADASIL syndrome. J Neurol Sci. 2006 Jul 15;246(1-2):123-30. Wang Z et al. NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL. J Neurol Neurosurg Psychiatry. 2011 May;82(5):534-9.
CeGaT Center for Human Genetics Tuebingen	RCV000516674	SCV001246159	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000516674	SCV001780161	pathogenic	not provided	2020-01-14	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32277177, 33061333, 31418856, 17996090, 26856460, 15387979, 9388399, 30311053, 28710804, 28991717, 24840674, 19167727, 25623805, 11706120, 25190493, 20935329, 29363903, 19174371, 19006080, 16730748, 11755616, 29188607, 29980472, 12721871)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000516674	SCV002176197	pathogenic	not provided	2023-12-28	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 110 of the NOTCH3 protein (p.Arg110Cys). 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 (PMID: 9388399, 29363903, 29980472). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447831). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000516674	SCV004225238	pathogenic	not provided	2023-01-05	criteria provided, single submitter	clinical testing	PP1, PP2, PP3, PP4, PM1, PM2, PS4
Institute of Human Genetics, University of Leipzig Medical Center	RCV000990179	SCV004698112	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2024-02-26	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM1,PM2_SUP,PP1,PP2,PP3
Molecular Genetics, Royal Melbourne Hospital	RCV000990179	SCV004812633	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2023-05-05	criteria provided, single submitter	clinical testing	This sequence change in NOTCH3 is predicted to replace arginine with cysteine at codon 110, p.(Arg110Cys). The arginine residue is moderately conserved (100 vertebrates, UCSC), and introduces an odd number of cysteine residues in the EGF-like repeat domain 2 which is expected to alter the disulfide bonds in this domain. 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 seven individuals with a clinical diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; PMID: 16730748, 9388399, 29363903, 33061333, 35775048). The variant has been reported to segregate with CADASIL in four affected family members from three unrelated families (PMID: 16730748, 29363903). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.757). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PM1, PP1_Moderate, PM2_Supporting, PP3.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000516674	SCV005197011	pathogenic	not provided	2024-02-16	criteria provided, single submitter	clinical testing
GenomeConnect - CureCADASIL	RCV000990179	SCV001156354	not provided	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1		no assertion provided	phenotyping only	Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 02-13-2015 by lab or GTR ID 303161. Variant interpreted as Uncertain Significance and reported on 05-28-2021 by lab or GTR ID 500105. GenomeConnect - CFC International 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000990179	SCV001367815	uncertain significance	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2019-01-09	flagged submission	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3,PP5.
PreventionGenetics, part of Exact Sciences	RCV004537853	SCV004725062	pathogenic	NOTCH3-related disorder	2024-06-20	no assertion criteria provided	clinical testing	The NOTCH3 c.328C>T variant is predicted to result in the amino acid substitution p.Arg110Cys. This variant has been reported as causative for CADASIL in numerous patients and families (see for example Joutel et al. 1997. PubMed ID: 9388399; Wang et al. 2011. PubMed ID: 20935329). Of note, the vast majority of 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, where this patient’s variant is located. This patient’s variant alters a cysteine residue and is located in the extracellular EGF-like domain two. 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 has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.