ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.1514G>A (p.Cys505Tyr) (rs1060502240)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000473399 SCV000548945 uncertain significance Adams-Oliver syndrome 5 2016-12-24 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 505 of the NOTCH1 protein (p.Cys505Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a NOTCH1-related disease. 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. This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)-like domain of the NOTCH1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 3495735, 4750422). In addition, missense substitutions affecting cysteine residues within NOTCH1 EGF-like domains are overrepresented among individuals affected with Adams-Oliver syndrome and/or congenital heart disease (PMID: 25132448, 25963545, 26820064) relative to the general population (ExAC). In summary, this variant is a novel missense change affecting a residue crucial for protein stability and function. Although cysteine substitutions located in NOTCH1 EGF-like domains are likely deleterious, further genetic and/or functional data is needed to conclusively interpret this variant. Therefore, it has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.