Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001246930 | SCV001420322 | uncertain significance | Adams-Oliver syndrome 5 | 2023-11-28 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 843 of the NOTCH1 protein (p.Glu843Lys). 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: 971201). 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 95%. 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 | RCV002430046 | SCV002742075 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-03-18 | criteria provided, single submitter | clinical testing | The p.E843K variant (also known as c.2527G>A), located in coding exon 16 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 2527. The glutamic acid at codon 843 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003331089 | SCV004037777 | uncertain significance | not specified | 2023-08-30 | criteria provided, single submitter | clinical testing | Variant summary: NOTCH1 c.2527G>A (p.Glu843Lys) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 247298 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2527G>A in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| ARUP Laboratories, |
RCV003738024 | SCV004563279 | uncertain significance | not provided | 2023-03-14 | criteria provided, single submitter | clinical testing | The NOTCH1 c.2527G>A; p.Glu843Lys variant (rs750170645), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 971201). This variant is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.152). Due to limited information, the clinical significance of this variant is uncertain at this time. |