ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1732C>T (p.Arg578Cys) (rs769773673)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000996814 SCV001151744 likely pathogenic not provided 2017-01-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285697 SCV001472173 likely pathogenic none provided 2019-08-27 criteria provided, single submitter clinical testing The NOTCH3 c.1732C>T; p.Arg578Cys variant (rs769773673) is reported in the literature in multiple individuals affected with CADASIL (Choi 2006, Joutel 1996, Liem 2008, Tikka 2009). In one family, this variant was found in two mildly affected sibilings, one homozygous and one heterozygous, and was absent from an unaffected sibling (Liem 2008). Additionally, this variant has been observed in a neuropathogically normal individual from an elderly control cohort with Alzheimer’s disease (Sassi 2018), suggesting this variant may exhibit incomplete penetrance. This variant is found in the general population with a low overall allele frequency of 0.004% (10/250688 alleles) in the Genome Aggregation Database. The arginine at codon 578 is highly conserved, it occurs in the fourteenth EGF-like domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014), and thus the p.Arg578Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Choi JC et al. Intracerebral hemorrhages in CADASIL. Neurology. 2006 Dec 12;67(11):2042-4. Joutel A et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996 Oct 24;383(6602):707-10. Liem MK et al. Homozygosity for a NOTCH3 mutation in a 65-year-old CADASIL patient with mild symptoms: a family report. J Neurol. 2008 Dec;255(12):1978-80. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Sassi C et al. Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3. Neurobiol Aging. 2018 Jun;66:179.e17-179.e29. Tikka S et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain. 2009 Apr;132(Pt 4):933-9.

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