ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.3529G>A (p.Gly1177Arg)

gnomAD frequency: 0.00001  dbSNP: rs754086177
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Total submissions: 4
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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 RCV001799351 SCV002043516 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-11-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV001799351 SCV002619035 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-07-23 criteria provided, single submitter clinical testing The p.G1177R variant (also known as c.3529G>A), located in coding exon 22 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 3529. The glycine at codon 1177 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV002463034 SCV002757709 uncertain significance not provided 2022-05-26 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 has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Labcorp Genetics (formerly Invitae), Labcorp RCV002544362 SCV003249108 uncertain significance Adams-Oliver syndrome 5 2022-05-03 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1329308). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. This variant is present in population databases (rs754086177, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1177 of the NOTCH1 protein (p.Gly1177Arg).

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