ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1565G>C (p.Cys522Ser)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002471320 SCV002767211 uncertain significance Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 2020-10-19 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as a 3A-VUS Following criteria are met: 0103 - Gain of function and dominant negative have been indicated as mechanisms of disease in this gene in association with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy 1) (MIM#125310) (PMID: 19293235, PMID: 23649698, PMID: 30032161). Loss of function has also been reported but considered less likely (PMID: 24425116). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The position of the variant in the NOTCH3 gene is the most important determinant of CADASIL disease severity (PMID: 27844030, PMID: 30032161). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2.1.1 and v3). (SP) 0309 - An alternative amino acid change at the same position, p.(Cys522Trp), has been observed in gnomAD (v2.1.1) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is very highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional calcium-binding EGF-like domain. The addition or elimination of cysteine residues in the EGF-like repeat domains typically result in mismatched disulphide bridging and altered protein function (PMID: 32196841). (SP) 0705 - No comparable missense variants at the same position have previous evidence for pathogenicity. However, several cysteine-altering variants nearby and throughout the gene have been reported to cause disease (ClinVar, HGMD, LOVD3). (I) 0807- This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign
Athena Diagnostics RCV003482413 SCV004229485 pathogenic not provided 2023-01-04 criteria provided, single submitter clinical testing This variant has been identified in at least one individual with clinical features associated with CADASIL. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). 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).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV003482413 SCV004562620 likely pathogenic not provided 2023-10-03 criteria provided, single submitter clinical testing The NOTCH3 c.1565G>C; p.Cys522Ser variant, is reported in the literature in two individuals affected with CADASIL (Rodriguez 2021, Zhang 2022). This variant is reported in ClinVar (Variation ID: 1804902), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.976). 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.Cys522Ser variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Rodriguez CA et al. A novel Notch 3 mutation (pathogenic variant c.1565G>C) in CADASIL. Neurologia (Engl Ed). 2021 May 29:S0213-4853(21)00081-5. English, Spanish. PMID: 34074565. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. PMID: 24844136. Zhang R et al. Elderly CADASIL patients with intact neurological status. J Stroke. 2022 Sep;24(3):352-362. PMID: 36221938.
Mayo Clinic Laboratories, Mayo Clinic RCV003482413 SCV005413343 likely pathogenic not provided 2024-04-19 criteria provided, single submitter clinical testing PP2, PP3, PM1, PM2, PM5, PS4_moderate

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