Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000655271 | SCV000777201 | uncertain significance | Adams-Oliver syndrome 5 | 2022-04-12 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 544194). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1301 of the NOTCH1 protein (p.Gly1301Arg). This variant also falls at the last nucleotide of exon 23, which is part of the consensus splice site for this exon. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 |
RCV003117457 | SCV003798937 | uncertain significance | not provided | 2022-08-05 | 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; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge |
| Ambry Genetics | RCV004822148 | SCV005456639 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2024-08-15 | criteria provided, single submitter | clinical testing | The p.G1301R variant (also known as c.3901G>A), located in coding exon 23 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 3901. The amino acid change results in glycine to arginine at codon 1301, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 23, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |