ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.3706C>T (p.Pro1236Ser) (rs749988739)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000553375 SCV000659429 uncertain significance Adams-Oliver syndrome 5 2017-01-25 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 1236 of the NOTCH1 protein (p.Pro1236Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. The frequency data for this variant (rs749988739) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported in an individual affected with bicuspid aortic valve and thoracic aortic aneurysm (PMID: 25907466). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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