ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.7115G>A (p.Arg2372Gln) (rs373119531)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000529611 SCV000659490 uncertain significance Adams-Oliver syndrome 5 2019-01-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 2372 of the NOTCH1 protein (p.Arg2372Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs373119531, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with NOTCH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV000620680 SCV000739507 uncertain significance Cardiovascular phenotype 2017-11-04 criteria provided, single submitter clinical testing The p.R2372Q variant (also known as c.7115G>A), located in coding exon 34 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 7115. The arginine at codon 2372 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000529611 SCV000782577 uncertain significance Adams-Oliver syndrome 5 2017-01-19 criteria provided, single submitter clinical testing

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