ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.1787C>T (p.Thr596Met) (rs61755997)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246067 SCV000320524 uncertain significance Cardiovascular phenotype 2015-11-27 criteria provided, single submitter clinical testing The p.T596M variant (also known as c.1787C>T), located in coding exon 11 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 1787. The threonine at codon 596 is replaced by methionine, an amino acid with similar properties. This variant (also referred to as c.1963 C>T)was reported in a patient with bicuspid aortic valve (Mohamed SA et al,Biochem.Biophys. Res.Commun.2006 Jul; 345(4):1460-5). This variant was previously reported in the SNPDatabase as rs61755997. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.02% (3/12930) total alleles studied, having been observed in 0.05% (2/4362) African American alleles and 0.01% (1/8568) European American alleles. Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project.This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000660144 SCV000782138 likely benign Connective tissue disease 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV001049180 SCV001213216 uncertain significance Adams-Oliver syndrome 5 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 596 of the NOTCH1 protein (p.Thr596Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs61755997, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with a bicuspid aortic valve (PMID: 16729972). ClinVar contains an entry for this variant (Variation ID: 264528). 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: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
GeneDx RCV001575577 SCV001802603 likely benign not provided 2021-06-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17662764, 16729972)
OMIM RCV000787043 SCV000925959 pathogenic Aortic valve disease 1 2006-07-14 no assertion criteria provided literature only

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