ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.3043T>C (p.Cys1015Arg) (rs1599382214)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000990176 SCV001141024 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001284773 SCV001470793 likely pathogenic none provided 2019-09-03 criteria provided, single submitter clinical testing The NOTCH3 c.3043T>C; p.Cys1015Arg variant is reported in the literature in multiple individuals affected with CADASIL (Oberstein 1999, Rutten 2016). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 1015 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This variant lies within 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). Additionally, another variant at this codon (c.3043T>A; p.Cys1015Ser) has been reported in individuals with CADASIL (Zhu 2015). Based on available information, this variant is considered to be likely 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. 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 J et al. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain. 2016 Apr;139(Pt 4):1123-35. Rutten JW et al. Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. Ann Clin Transl Neurol. 2016 Sep 28;3(11):844-853. Zhu Y et al. Two novel mutations in NOTCH3 gene causes cerebral autosomal dominant arteriopathy with subcritical infarct and leucoencephalopathy in two Chinese families. Int J Clin Exp Pathol. 2015 Feb 1;8(2):1321-7.

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