ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.2437G>A (p.Glu813Lys)

gnomAD frequency: 0.00020  dbSNP: rs375873637
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV001644606 SCV000614256 likely benign not specified 2020-10-07 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV002223221 SCV002501370 uncertain significance not provided 2021-04-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002223221 SCV003254432 benign not provided 2022-02-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV002223221 SCV003799305 uncertain significance not provided 2022-04-28 criteria provided, single submitter clinical testing The NOTCH3 c.2437G>A; p.Glu813Lys variant (rs375873637), to our knowledge, is not reported in the medical literature in an affected individual, but is reported in ClinVar (Variation ID: 447811). This variant is found in the African/African-American population with an allele frequency of 0.06% (14/24,936 alleles) in the Genome Aggregation Database. The glutamic acid at codon 813 is highly conserved, occurs in an EGF-like domain, and computational analyses predict that this variant is deleterious (REVEL: 0.89). In support of this prediction, computational modeling indicates this vriant may alter the protein structure (Vlachakis 2014). Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). However, there are several amino acid substitutions not involving cysteine that may be disease-associated (Muino 2017). Due to limited information, the clinical significance of the p.Glu813Lys variant is uncertain at this time. References: Muino E et al. Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL. Int J Mol Sci. 2017 Sep 13;18(9). pii: E1964. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Vlachakis D et al. A series of Notch3 mutations in CADASIL; insights from 3D molecular modelling and evolutionary analyses. J Mol Biochem. 2014;3(3):134. PMID: 31799216.
Revvity Omics, Revvity RCV002223221 SCV003816020 uncertain significance not provided 2019-10-25 criteria provided, single submitter clinical testing

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