Submissions for variant NM_017617.5(NOTCH1):c.4412C>G (p.Ala1471Gly)

dbSNP: rs376799353

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001879269	SCV002141694	uncertain significance	Adams-Oliver syndrome 5	2021-10-23	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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) performed at Invitae indicates that this missense variant is not expected to disrupt NOTCH1 protein function. This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. This sequence change replaces alanine with glycine at codon 1471 of the NOTCH1 protein (p.Ala1471Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine.