ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.3269C>G (p.Thr1090Ser)

gnomAD frequency: 0.00002  dbSNP: rs761508282
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000655241 SCV000777171 uncertain significance Adams-Oliver syndrome 5 2024-05-13 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 1090 of the NOTCH1 protein (p.Thr1090Ser). This variant is present in population databases (rs761508282, gnomAD 0.002%). This missense change has been observed in individual(s) with aortic valve calcification and severe calcification and dysfunction of tricuspid aortic valve (PMID: 23102684). ClinVar contains an entry for this variant (Variation ID: 544171). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NOTCH1 protein function with a negative predictive value of 80%. 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 RCV003226964 SCV003923716 uncertain significance not provided 2024-04-15 criteria provided, single submitter clinical testing Reported in a patient with bicuspid aortic valve in the published literature (PMID: 23102684); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23102684, 30371227)

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