ClinVar

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. ClinVar contains an entry for this variant (Variation ID: 1367342). This missense change has been observed in individual(s) with clinical features of NOTCH3-related conditions (PMID: 31915071, 32555735). This variant is present in population databases (rs761407832, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 239 of the NOTCH3 protein (p.Asp239Asn).