ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 437 of the ENG protein (p.Arg437Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 21158752, 25970827, 30946035; Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Arg437 amino acid residue in ENG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16752392, 21158752, 23535011; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Identified in patients with HHT referred for genetic testing at GeneDx and in published literature (PMID: 21158752, 30946035, 25970827); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21158752, 25970827, 30279913, 30946035)