ClinVar Miner

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

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Total submissions: 4
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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 Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence
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 2019-12-12 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.
OMIM RCV000787043 SCV000925959 pathogenic Aortic valve disorder 2006-07-14 no assertion criteria provided literature only

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