ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.268C>T (p.Arg90Cys) (rs1555729604)

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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 RCV000518819 SCV000614262 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000760969 SCV000890869 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2016-09-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000930 SCV001158023 pathogenic not specified 2018-11-20 criteria provided, single submitter clinical testing The NOTCH3 c.268C>T; p.Arg90Cys variant has been described in several individuals and families affected with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome (Joutel 1997, Lackovic 2012, Lian 2013, Utku 2002). It contains an entry in ClinVar (Variation ID: 447816), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. 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). Functional studies of the variant protein demonstrate reduced cell viability and aberrant NOTCH3 proteolytic processing in oligodendrocytes, and enhanced cortical susceptibility to spreading depression in mice (Eikermann-Haerter 2011, Tang 2017). Based on available information, this variant is considered 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. Eikermann-Haerter K et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression. Ann Neurol. 2011 Feb;69(2):413-8. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. 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. Lian L et al. Spontaneous intracerebral hemorrhage in CADASIL. J Headache Pain. 2013 Dec 17;14:98. 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. Tang M et al. CADASIL mutant NOTCH3(R90C) decreases the viability of HS683 oligodendrocytes via apoptosis. Mol Biol Rep. 2017 Jul;44(3):273-280. Utku U et al. CADASIL syndrome in a large Turkish kindred caused by the R90C mutation in the Notch3 receptor. Eur J Neurol. 2002 Jan;9(1):23-8.

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