Submissions for variant NM_017617.5(NOTCH1):c.4010C>G (p.Pro1337Arg) (rs1043832212)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000617671	SCV000739505	uncertain significance	Cardiovascular phenotype	2017-10-20	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence
GeneDx	RCV000481924	SCV000572747	uncertain significance	not provided	2017-02-07	criteria provided, single submitter	clinical testing	The P1337R variant in the NOTCH1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P1337R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P1337R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P1337R as a variant of uncertain significance.
Invitae	RCV000655253	SCV000777183	uncertain significance	Adams-Oliver syndrome 5	2017-08-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline with arginine at codon 1337 of the NOTCH1 protein (p.Pro1337Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NOTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 423102). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.