Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000468891 | SCV000548930 | uncertain significance | Adams-Oliver syndrome 5 | 2024-01-13 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1675 of the NOTCH1 protein (p.Ile1675Val). This variant is present in population databases (rs375408767, gnomAD 0.005%). 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: 409049). 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. |
Gene |
RCV001546235 | SCV001765722 | uncertain significance | not provided | 2020-12-10 | 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 |
Genome- |
RCV000468891 | SCV002553373 | uncertain significance | Adams-Oliver syndrome 5 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV002270498 | SCV002553374 | uncertain significance | Aortic valve disease 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002348311 | SCV002645524 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2022-01-12 | criteria provided, single submitter | clinical testing | The p.I1675V variant (also known as c.5023A>G), located in coding exon 27 of the NOTCH1 gene, results from an A to G substitution at nucleotide position 5023. The isoleucine at codon 1675 is replaced by valine, an amino acid with highly 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. |