ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000763038 SCV000893515 likely pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; Lehman syndrome; Infantile myofibromatosis 2 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000657880 SCV000779643 likely pathogenic not provided 2018-05-22 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the NOTHC3 gene. The R544C variant has been reported previously in association with CADASIL in multiple Asian families, and is considered to be the result of a founder effect in this population (Liao et al., 2015; Lee et al., 2015; Soong et al., 2013). The R544C variant is observed in 72/18844 (0.4%) alleles from individuals of East Asian background (Lek et al., 2016). The R544C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The R544C variant is located in a critical functional domain. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
GeneReviews RCV000778145 SCV000987226 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy 2019-02-19 no assertion criteria provided literature only
Illumina Clinical Services Laboratory,Illumina RCV000778145 SCV000914276 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy 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.

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