ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.505C>T (p.Arg169Cys) (rs28933696)

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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 RCV000518159 SCV000614307 pathogenic not provided 2018-06-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001173 SCV001158324 pathogenic none provided 2020-06-09 criteria provided, single submitter clinical testing The NOTCH3 c.505C>T; p.Arg169Cys variant (rs28933696) is reported in the medical literature in individuals with CADASIL (Lynch 2017, Opherk 2004, Paraskevas 2014). Additionally, a mouse model with this variant shows hallmarks of disease (Cognat 2014). The variant is described in the ClinVar database (Variation ID: 9219) 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 arginine at this position is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as pathogenic. References: Cognat E et al. Archetypal Arg169Cys mutation in NOTCH3 does not drive the pathogenesis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy via a loss-of-function mechanism. Stroke. 2014 Mar;45(3):842-9. Lynch DS et al. Clinical and genetic characterization of leukoencephalopathies in adults. Brain. 2017 May 1;140(5):1204-1211. Opherk C et al. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004 Nov;127(Pt 11):2533-9. Paraskevas GP et al. CADASIL and autoimmunity: coexistence in a family with the R169C mutation at exon 4 of the NOTCH3 gene. Cerebrovasc Dis. 2014;38(4):302-7.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000518159 SCV001249857 pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000009800 SCV001428923 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2018-01-16 criteria provided, single submitter clinical testing
OMIM RCV000009800 SCV000030021 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 1997-11-22 no assertion criteria provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003548 SCV001161892 likely pathogenic Migraine without aura; Stroke no assertion criteria provided research

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