ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.6481C>T (p.Pro2161Ser) (rs201518848)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000727124 SCV000617310 uncertain significance not provided 2017-10-30 criteria provided, single submitter clinical testing The P2161S variant in the NOTCH1 gene has been reported previously in an individual with bicuspid aortic valve (Bonachea et al., 2014). This variant is observed in 14/125276 (0.0011%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The P2161S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P2161S as a variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727124 SCV000705953 uncertain significance not provided 2017-03-17 criteria provided, single submitter clinical testing
Invitae RCV001058437 SCV001223010 uncertain significance Adams-Oliver syndrome 5 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 2161 of the NOTCH1 protein (p.Pro2161Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs201518848, ExAC 0.01%). This variant has been observed in an individual with bicuspid aortic valve (PMID: 25260786). ClinVar contains an entry for this variant (Variation ID: 449324). 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 C65"). 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.

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