ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.7033G>A (p.Gly2345Ser)

gnomAD frequency: 0.00001  dbSNP: rs1325758824
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002315102 SCV000739455 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-12-02 criteria provided, single submitter clinical testing The p.G2345S variant (also known as c.7033G>A), located in coding exon 34 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 7033. The glycine at codon 2345 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. 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.
GeneDx RCV001591391 SCV001826799 uncertain significance not provided 2021-01-15 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance, but additional evidence is not available (ClinVar Variant ID# 520058; Landrum et al., 2016)
Genome-Nilou Lab RCV002270898 SCV002553264 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002270897 SCV002553265 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002270898 SCV004382866 uncertain significance Adams-Oliver syndrome 5 2025-01-26 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2345 of the NOTCH1 protein (p.Gly2345Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 520058). 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.

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