ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.2636G>A (p.Arg879Gln) (rs368011392)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523567 SCV000621033 uncertain significance not provided 2018-05-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The R879Q variant has been reported as a variant of uncertain significance in one patient with aortopathy (Yang et al., 2016). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R879Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and where glutamine (Q) is present as the wild type in at least one species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000476977 SCV000548917 uncertain significance Adams-Oliver syndrome 5 2017-03-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 879 of the NOTCH1 protein (p.Arg879Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs368011392, ExAC 0.02%). This variant has been reported in an individual affected with hypoplastic left heart syndrome (PMID: 26820064). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The glutamine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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