ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1973T>C (p.Ile658Thr)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002615606 SCV003501384 likely benign not provided 2024-12-09 criteria provided, single submitter clinical testing
Athena Diagnostics RCV002615606 SCV005621511 uncertain significance not provided 2024-01-05 criteria provided, single submitter clinical testing Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools predict that this variant is damaging. 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 RCV002615606 SCV005877885 uncertain significance not provided 2024-03-21 criteria provided, single submitter clinical testing The NOTCH3 c.1973T>C; p.Ile658Thr variant (rs779379912), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 2183713). This variant is found in the general population with an overall allele frequency of 0.003% (7/282,072 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.827). 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). Although p.Ile658Thr does not involve a cysteine residue, due to limited information the clinical significance of this 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. PMID: 28902129.

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