ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1774C>T (p.Arg592Cys)

dbSNP: rs764148985
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000996813 SCV001151743 likely pathogenic not provided 2024-01-01 criteria provided, single submitter clinical testing NOTCH3: PM1:Strong, PM2, PS4:Moderate
Athena Diagnostics Inc RCV000996813 SCV001475692 pathogenic not provided 2023-03-30 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with CADASIL. In some published literature, this variant is referred to as c.1852C>T. 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).
Invitae RCV000996813 SCV002123466 pathogenic not provided 2022-10-07 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 808495). This missense change has been observed in individuals with clinical features of CADASIL (PMID: 19488902, 20167921, 22664156; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 592 of the NOTCH3 protein (p.Arg592Cys).
Institute of Human Genetics, University of Leipzig Medical Center RCV002267627 SCV002549828 likely pathogenic Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 2022-06-07 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PS4_MOD, PM1, PM2_SUP, PP3

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