ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.3658C>T (p.Arg1220Trp)

gnomAD frequency: 0.00036  dbSNP: rs115872852
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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 RCV000878820 SCV001021795 likely benign not provided 2021-08-06 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000878820 SCV001143381 benign not provided 2019-05-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000878820 SCV001472101 uncertain significance not provided 2020-08-07 criteria provided, single submitter clinical testing The NOTCH3 c.3658C>T; p.Arg1220Trp variant (rs115872852), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 707700). This variant is found in the African population with an allele frequency of 0.12% (30/24834 alleles) in the Genome Aggregation Database. The arginine at codon 1220 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. 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 the p.Arg1220Trp does not involve a cysteine residue, due to the lack of clinical and functional data, its clinical significance is uncertain. 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.

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