ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1531T>A (p.Cys511Ser)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV003482627 SCV004229484 pathogenic not provided 2023-08-30 criteria provided, single submitter clinical testing This variant has been identified in at least one individual with clinical features associated with this gene. 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 RCV003482627 SCV004565070 likely pathogenic not provided 2023-03-31 criteria provided, single submitter clinical testing The NOTCH3 c.1531T>A; p.Cys511Ser variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (p.Cys511Arg, p.Cys511Phe, p.Cys511Tyr) have been reported in individuals with (CADASIL) and are considered pathogenic (Opherk 2004; Mosca 2011; Bianchi 2005). Computational analyses predict that this variant is deleterious (REVEL: 0.948). 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.Cys511Ser variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Bianchi S et al. Gene symbol: Notch3. Disease: CADASIL. Hum Genet. 2005 Dec;118(3-4):546. Mosca L et al. NOTCH3 gene mutations in subjects clinically suspected of CADASIL. J Neurol Sci. 2011 Aug 15;307(1-2):144-8. PMID: 21616505. Opherk C et al. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004 Nov;127(Pt 11):2533-9. PMID: 15364702. 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.
GeneDx RCV003482627 SCV005380128 uncertain significance not provided 2023-10-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24844136)

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