Submissions for variant NM_000435.3(NOTCH3):c.1630C>T (p.Arg544Cys)

gnomAD frequency: 0.00010  dbSNP: rs201118034

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657880	SCV000779643	likely pathogenic	not provided	2020-04-06	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24344756, 25095812, 21852154, 28549449, 31515791, 23847153, 18207319, 24480794, 19252787, 23602593, 16580020, 17135568, 10371548, 26002683, 22133740, 24139282, 27844030, 25105908, 26671140, 28710804, 26308724, 25692567, 25959358, 19242647, 30199759, 30656190, 31792094, 32410215, 32277177)
Fulgent Genetics, Fulgent Genetics	RCV000763038	SCV000893515	likely pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1; Lateral meningocele syndrome; Myofibromatosis, infantile, 2	2021-11-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778145	SCV000914276	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2019-04-05	criteria provided, single submitter	clinical testing	The NOTCH3 c.1630C>T (p.Arg544Cys) missense variant has been reported extensively in the literature, particularly in individuals affected with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) of Asian descent, where the variant appears to be a founder variant (Lee et al. 2009; Choi et al. 2013; Liao et al. 2015). Across a selection of the available literature, the p.Arg544Cys variant has been identified in 155 individuals affected with CADASIL, including four individuals who were homozygous for the variant (Oberstein et al. 1999; Lee et al. 2009b; Choi et al. 2013; Soong et al. 2013; Kim et al. 2014; Liao et al. 2015). Of note, the expressivity of CADASIL varies in age of onset, severity of clinical symptoms and progression of disease (Rutten et al. 2000). The p.Arg544Cys variant was absent from 100 controls and is reported at a frequency of 0.003821 in the East Asian population of the Genome Aggregation Database. Based on the evidence, the p.Arg544Cys variant is classified as pathogenic for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657880	SCV001473517	likely pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing	The NOTCH3 c.1630C>T; p.Arg544Cys variant (rs201118034) is reported in the literature in several individuals with CADASIL and segregates with disease in families (Choi 2013, Liao 2015, Tang 2018, Yoon 2015). The variant exhibits a founder effect in Asians (Liao 2015) and is reported in the East Asian population with an allele frequency of 0.4% (79/19916 alleles) in the Genome Aggregation Database. The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 546089). The arginine at codon 544 computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly Damaging) predict conflicting effects of this variant on protein structure/function. However, this variant creates a cysteine in an EGF-like domain and most pathogenic NOTCH3 variants create or destroy a cysteine residue within an EGF-like domain (Rutten 2014); thus, the p.Arg544Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Considering available information, this variant is classified as likely pathogenic. REFERENCES Choi JC et al. Diversity of stroke presentation in CADASIL: study from patients harboring the predominant NOTCH3 mutation R544C. J Stroke Cerebrovasc Dis. 2013 Feb;22(2):126-31. Liao YC et al. Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles. PLoS One. 2015 Aug 26;10(8):e0136501. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Tang SC et al. Prevalence and clinical characteristics of stroke patients with p.R544C NOTCH3 mutation in Taiwan. Ann Clin Transl Neurol. 2018 Nov 20;6(1):121-128. Yoon CW et al. NOTCH3 variants in patients with subcortical vascular cognitive impairment: a comparison with typical CADASIL patients. Neurobiol Aging. 2015 Aug;36(8):2443.e1-7.
Athena Diagnostics	RCV000657880	SCV001475690	pathogenic	not provided	2023-05-22	criteria provided, single submitter	clinical testing	This variant is the most common variant associated with CADASIL in the East Asian population (PMID: 25692567, 26308724, 31792094), and is statistically more frequent in affected individuals than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Reports of this variant in asymptomatic individuals, as well as affected heterozygous and homozygous patients, suggests this variant may have reduced penetrance (PMID: 26308724, 30199759, 30656190, 31792094). 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 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).
Revvity Omics, Revvity	RCV000657880	SCV002020141	likely pathogenic	not provided	2021-09-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805784	SCV002051334	pathogenic	Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy	2021-12-23	criteria provided, single submitter	clinical testing	Variant summary: NOTCH3 c.1630C>T (p.Arg544Cys) results in a non-conservative amino acid change at a location bordered between the EGFR-13 and EGFR-14 domains (IPR000742) of the encoded protein sequence. This is different from other cysteine involving mutations residing within an EGFR domain and therefore, comparing with other cysteine-involving NOTCH3 mutations, R544C may result in a milder conformational change of NOTCH3 molecules and consequently a milder clinical phenotype (Liao_2015). Gain/loss of cysteine residues in the EGFr domains in NOTCH3 have been shown to be typical mutations of CADASIL and NOTCH3-related disorders (reviewed by Mizuno_2020). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 250312 control chromosomes, particularly at a frequency of 0.0041 within the East Asian subpopulation in the gnomAD database. c.1630C>T has been reported in the literature in multiple individuals/families (mainly of East Asian origin) affected with CADASIL and NOTCH3-Related Disorders (example: Oberstein_1999, Kim_2006, Soong_2013, Liao_2015). Asymptomatic individuals with the variant have also been reported within affected families (example: Kim_2006, Liao_2015). Recent data suggest that CADASIL is much more prevalent than previously suspected and the NOTCH3 clinical spectrum must be considerably broader, ranging from classic CADASIL to a much milder small-vessel disease, or possibly even non-penetrance (Hack RJ, Rutten J, Lesnik Oberstein SAJ. CADASIL. 2000 Mar 15 [Updated 2019 Mar 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed this variant since 2014: four have classified the variant as likely pathogenic and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion	RCV000778145	SCV002058228	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2022-01-03	criteria provided, single submitter	clinical testing	The variant known to cause Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 in an autosomal dominant inheritance pattern. The variant the most common variant associated with CADASIL in the East Asian population (PMID: 25692567, 26308724, 31792094). It has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 32277177, 30906334, 25692567, 26308724, 31792094, PS4_S). A missense variant is a common mechanism associated with Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657880	SCV002242127	pathogenic	not provided	2023-11-21	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 544 of the NOTCH3 protein (p.Arg544Cys). This variant is present in population databases (rs201118034, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 16717210, 19242647, 26308724, 30906334, 31792094). It is commonly reported in individuals of East Asian ancestry (PMID: 19242647). ClinVar contains an entry for this variant (Variation ID: 546089). 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	RCV000778145	SCV002517806	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2022-05-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000778145	SCV002767997	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Both loss of function and dominant negative have been suggested as mechanisms in CADASIL (MIM#125310), however lateral meningocele syndrome (MIM#130720) results from a gain of function (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The p.(Arg544Cys) variant is associated with a later age of onset and milder clinical features than other NOTCH3 variants (GeneReviews, PMID: 26308724). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v3) (8 heterozygotes, 0 homozygotes). (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (83 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This is considered to be a founder variant in East Asian populations and is one of the most common NOTCH3 variants, having been identified in over 100 individuals and families with CADASIL (MIM#125310) (ClinVar, HGMD, LOVD, PMIDs: PMID: 26308724, 30656190). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneReviews	RCV000778145	SCV000987226	not provided	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1		no assertion provided	literature only