ClinVar Genomic variation as it relates to human health

BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 295 of the IL10RA protein (p.Pro295Leu). This variant is present in population databases (rs56143179, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with inflammatory bowel disease (PMID: 29248579, 33359885; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 538051). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IL10RA protein function. 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.

The VUS detected here is a missense variant that leads to an exchange of the amino acid proline, which is weakly conserved at the site, for leucine. In the LOVD shared database the variant is listed as VUS or probably benign, in the ClinVar database (e.g. SCV000768990.7) the variant is evaluated as VUS. In the gnomAD population database, an allele frequency of 0.08% is reported for the variant (gnomAD; ALL). An in silico analysis of this variant using the REVEL program suggests that it may be a variant without clinical significance.

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Identified in a patient with very onset inflammatory bowel disease (Girardelli et al., 2018); This variant is associated with the following publications: (PMID: 29248579)

IL10RA: BP4, BS1