ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1364G>A (p.Cys455Tyr) (rs886041513)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518543 SCV000614222 pathogenic not provided 2019-09-25 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000977 SCV001158077 likely pathogenic not specified 2018-12-26 criteria provided, single submitter clinical testing The NOTCH3 c.1364G>A; p.Cys455Tyr variant (rs886041513), is reported in the literature in at least one individual affected with CADASIL (Kim 2014). This variant is reported in ClinVar (Variation ID: 447784), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 455 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.1363C>T, p.Cys455Arg) has been reported in individuals with CADASIL and is considered pathogenic (Arboleda-Velasquez 2002). Based on available information, the p.Cys455Tyr variant is considered to be likely pathogenic. References: Arboleda-Velasquez JF et al. C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke. Neurology. 2002 Jul 23;59(2):277-9. 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. Kim YE et al. Spectrum of NOTCH3 mutations in Korean patients with clinically suspicious cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Neurobiol Aging. 2014 Mar;35(3):726.e1-6. 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.

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