ClinVar Miner

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

dbSNP: rs75068032
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Total submissions: 8
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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 arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1; Lateral meningocele syndrome; Myofibromatosis, infantile, 2 2018-10-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000517370 SCV001473496 likely pathogenic not provided 2020-10-02 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 arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001526580 SCV001934510 likely pathogenic Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 2021-04-06 criteria provided, single submitter clinical testing Despite strong evidence for its pathogenicity, this variant has to be classified as of unknown significance, according to the ACMG-criteria (Richards et al., 2015)
GeneDx RCV000517370 SCV002038909 likely pathogenic not provided 2021-12-20 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8878478, 29757481, 9388399, 11102981, 15364702, 16009764, 24086431, 19174371, 27844030, 23844775, 11755616, 22218279, 25929831, 28710804, 31028544, 33130454, 32172663, 29188608, 31589614, 34851492, 24844136, 31146726, Cebi2021[Article], Rustemoglu2021[article])
Invitae RCV000517370 SCV002237220 pathogenic not provided 2021-11-20 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 558 of the NOTCH3 protein (p.Arg558Cys). This variant is present in population databases (rs75068032, gnomAD 0.005%). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 8878478, 16009764, 23844775, 32172663). This variant is also known as CGC>TGC; R>C in N12. ClinVar contains an entry for this variant (Variation ID: 447794). 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. For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002252148 SCV002523155 likely pathogenic See cases 2021-05-24 criteria provided, single submitter clinical testing ACMG classification criteria: PS4, PM1, PM2

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