ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4472C>T (p.Thr1491Met) (rs369915496)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471927 SCV000548942 uncertain significance Adams-Oliver syndrome 5 2020-03-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1491 of the NOTCH1 protein (p.Thr1491Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs369915496, ExAC 0.01%). This variant has been observed in an individual with bicuspid aortic valve (PMID: 26708639). ClinVar contains an entry for this variant (Variation ID: 409060). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C1). 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. 5
Ambry Genetics RCV000621410 SCV000739410 uncertain significance Cardiovascular phenotype 2016-03-09 criteria provided, single submitter clinical testing The p.T1491M variant (also known as c.4472C>T), located in coding exon 25 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 4472. The threonine at codon 1491 is replaced by methionine, an amino acid with some similar properties. This alteration has been reported in one patient with bicuspid aortic valve (BAV) (Dargis N, Am. J. Cardiol. 2016 Feb; 117(3):420-6). This variant was previously reported in the SNPDatabase as rs369915496. Based on data from ExAC, the T allele has an overall frequency of less than 0.01% (2/103014). Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.01% (1/12820) total alleles studied and 0.01% (1/8502) European American alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics,Fulgent Genetics RCV000766058 SCV000897514 uncertain significance Aortic valve disease 1; Adams-Oliver syndrome 5 2018-10-31 criteria provided, single submitter clinical testing

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.