ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.6593C>T (p.Ser2198Leu) (rs761562076)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619172 SCV000739429 uncertain significance Cardiovascular phenotype 2016-06-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000227496 SCV000290299 uncertain significance Adams-Oliver syndrome 5 2016-01-18 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 2198 of the NOTCH1 protein (p.Ser2198Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs761562076, ExAC <0.01%) but 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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