ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1345C>T (p.Arg449Cys) (rs762734007)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289876 SCV001477875 likely pathogenic none provided 2020-03-27 criteria provided, single submitter clinical testing The NOTCH3 c.1345C>T; p.Arg449Cys variant is reported in the literature in association with CADASIL, but without specific patient information (Kalimo 2002). This variant is reported in ClinVar (Variation ID: 810777), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 449 is highly conserved, occurs in an EGF-like domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014), and thus the p.Arg449Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Kalimo H et al. CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol. 2002 Jul;12(3):371-84. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603.
GenomeConnect - CureCADASIL RCV000999636 SCV001156355 not provided Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 09-18-2015 by Lab or GTR ID 1012. 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.

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