ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1672C>T (p.Arg558Cys) (rs75068032)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517370 SCV000614235 pathogenic not provided 2019-05-14 criteria provided, single submitter clinical testing The variant disrupts a cysteine residue in an EGF-like repeat domain, which are important for the structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. Predicted to have a damaging effect on the protein. Co-occurs with otherwise positive results less than expected.
Fulgent Genetics,Fulgent Genetics RCV000763037 SCV000893514 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1; Lateral meningocele syndrome; Infantile myofibromatosis 2 2018-10-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286875 SCV001473496 likely pathogenic none provided 2020-07-07 criteria provided, single submitter clinical testing The NOTCH3 c.1672C>T; p.Arg558Cys variant (rs75068032) is reported in the literature in multiple individuals with a diagnosis or symptoms of CADASIL (Anamnart 2019, Chitnis 2012, Joutel 1996). This variant is found on only nine chromosomes in the Genome Aggregation Database (9/282416 alleles) and is reported as pathogenic by several laboratories in ClinVar (Variation ID: 447794). The arginine at codon 558 is highly conserved, it occurs in the 14th 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.Arg558Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Anamnart C et al. A large number of cerebral microbleeds in CADASIL patients presenting with recurrent seizures: a case report. BMC Neurol. 2019 May 30;19(1):106. Chitnis T and Hollmann TJ. CADASIL mutation and Balo concentric sclerosis: a link between demyelination and ischemia? Neurology. 2012 Jan 17;78(3):221-3. 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. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001526580 SCV001737007 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 criteria provided, single submitter clinical testing

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