ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.544C>T (p.Arg182Cys) (rs28933697)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517955 SCV000614313 pathogenic not provided 2017-11-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002285 SCV001160168 pathogenic not specified 2018-12-12 criteria provided, single submitter clinical testing The NOTCH3 c.544C>T; p.Arg182Cys variant (rs28933697), is reported in the literature in multiple individuals affected with CADASIL (Joutel 1997, Joutel 2000, Oberstein 1999). This variant is reported as pathogenic in ClinVar (Variation ID: 9220), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 182 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This variant lies with an EGF-like repeat domain, and pathogenic variants resulting in the gain or loss of a cysteine residue are common in these repeats and are predicted to disrupt protein structure (Dichgans 2000, Joutel 1997, Rutten 2016). Based on available information, the p.Arg182Cys variant is considered to be pathogenic. References: Dichgans M et al. Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet. 2000 Apr;8(4):280-5. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Joutel A et al. De novo mutation in the Notch3 gene causing CADASIL. Ann Neurol. 2000 Mar;47(3):388-91. Oberstein SA et al. Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. Neurology. 1999 Jun 10;52(9):1913-5. Rutten JW et al. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain. 2016 Apr;139(Pt 4):1123-35.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000517955 SCV001249854 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
OMIM RCV000009801 SCV000030022 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2000-03-01 no assertion criteria provided literature only
GenomeConnect - CureCADASIL RCV000009801 SCV001156358 not provided Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 no assertion provided phenotyping only Variant interpreted as Pathogenic and reported most recently on 05-09-2018 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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