Submissions for variant NM_000435.3(NOTCH3):c.6092G>A (p.Arg2031His)

gnomAD frequency: 0.00004  dbSNP: rs779314594

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001288544	SCV001473194	uncertain significance	not provided	2019-07-23	criteria provided, single submitter	clinical testing	The NOTCH3 c.6092G>A; p.Arg2031His variant (rs779314594), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the general population with an overall allele frequency of 0.006% (15/259256 alleles) in the Genome Aggregation Database. The arginine at codon 2031 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. 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.Arg2031His variant does not occur within this critical region or involve a cysteine residue, due to its low population frequency and conservation, its clinical significance is uncertain at this time. 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.
Athena Diagnostics Inc	RCV001288544	SCV001475724	likely benign	not provided	2020-02-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001288544	SCV004140291	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	NOTCH3: PP2, BP4, BS1:Supporting