ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1630C>T (p.Arg544Cys) (rs201118034)

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Total submissions: 6
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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 autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1; Lateral meningocele syndrome; Infantile myofibromatosis 2 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778145 SCV000914276 pathogenic Cerebral autosomal dominant arteriopathy 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 RCV001286893 SCV001473517 likely pathogenic none 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 Inc RCV000657880 SCV001475690 pathogenic not provided 2021-02-08 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 (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 alters a critical location within the protein, and is expected to severely affect function and cause disease. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Greater than 90% of NOTCH3 pathogenic mutations associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673).
GeneReviews RCV000778145 SCV000987226 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2019-02-19 no assertion criteria provided literature only

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