ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4549G>A (p.Asp1517Asn)

dbSNP: rs1554727954
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre of Medical Genetics, University of Antwerp RCV000662252 SCV000747173 likely pathogenic Adams-Oliver syndrome 5 2017-12-01 criteria provided, single submitter research
GeneDx RCV003223659 SCV003919493 likely pathogenic not provided 2022-10-20 criteria provided, single submitter clinical testing 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: 28191890, 28991257, 32368696, 26785492, 29924900)
Invitae RCV000662252 SCV004295622 pathogenic Adams-Oliver syndrome 5 2024-01-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1517 of the NOTCH1 protein (p.Asp1517Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Adams–Oliver syndrome and/or congenital heart disease (PMID: 12774039, 26785492, 29924900, 31941532). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 523598). 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 expected to disrupt NOTCH1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

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