ClinVar Miner

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

dbSNP: rs1555729604
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518819 SCV000614262 pathogenic not provided 2023-02-02 criteria provided, single submitter clinical testing This variant has been identified in multiple unrelated individuals with clinical features associated with CADASIL. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of NOTCH3 pathogenic variants associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673).
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000760969 SCV000890869 pathogenic Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 2016-09-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000518819 SCV001158023 pathogenic not provided 2020-11-08 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.
CeGaT Center for Human Genetics Tuebingen RCV000518819 SCV001961793 pathogenic not provided 2021-09-01 criteria provided, single submitter clinical testing
Invitae RCV000518819 SCV002148904 pathogenic not provided 2023-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 90 of the NOTCH3 protein (p.Arg90Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PMID: 9388399, 11784372, 23064698, 31813735). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447816). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NOTCH3 protein function. Experimental studies have shown that this missense change affects NOTCH3 function (PMID: 14714274, 21387384, 23028706, 28601945). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000518819 SCV004225249 pathogenic not provided 2022-08-29 criteria provided, single submitter clinical testing PP1, PP3, PP4, PM1, PM2, PS4

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