ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.2243C>A (p.Thr748Asn)

gnomAD frequency: 0.00001  dbSNP: rs1284149123
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000770642 SCV000902094 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2017-09-21 criteria provided, single submitter clinical testing
GeneDx RCV001799707 SCV002044025 uncertain significance not provided 2024-01-23 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27535533)
Genome-Nilou Lab RCV002271035 SCV002553569 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002271034 SCV002553571 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002271035 SCV003472467 uncertain significance Adams-Oliver syndrome 5 2024-11-11 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 748 of the NOTCH1 protein (p.Thr748Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 626873). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics RCV000770642 SCV004008079 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-03-31 criteria provided, single submitter clinical testing The p.T748N variant (also known as c.2243C>A), located in coding exon 14 of the NOTCH1 gene, results from a C to A substitution at nucleotide position 2243. The threonine at codon 748 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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