ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.194G>C (p.Cys65Ser) (rs1555730176)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517084 SCV000614246 pathogenic not provided 2019-08-23 criteria provided, single submitter clinical testing The variant disrupts a cysteine residue in an EGF-like repeat domain, which is important for the structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Institute of Human Genetics, University of Leipzig Medical Center RCV001253000 SCV001428498 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2018-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287684 SCV001474396 likely pathogenic none provided 2019-07-30 criteria provided, single submitter clinical testing The NOTCH3 c.194G>C; p.Cys65Ser variant is reported in the literature in individuals affected with CADASIL (Opherk 2004, Peters 2005). This variant is reported in ClinVar (Variation ID: 447803), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 65 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.193T>G; p.Cys65Gly, c.194G>A; p.Cys65Tyr) have been reported in individuals with CADASIL (Bianchi 2007, Cleves 2010, Lackovic 2012). Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). Based on available information, the p.Cys65Ser variant is considered to be likely pathogenic. References: Bianchi S et al. Novel human pathological mutations. Gene symbol: NOTCH3. Disease: CADASIL, exon 2 mutation. Hum Genet. 2007 Dec;122(5):558-9. Cleves C et al. Genetically confirmed CADASIL in a pediatric patient. Pediatrics. 2010 Dec;126(6):e1603-7. Lackovic V et al. Skin and sural nerve biopsies: ultrastructural findings in the first genetically confirmed cases of CADASIL in Serbia. Ultrastruct Pathol. 2012 Oct;36(5):325-35. 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. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603.

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