ClinVar Genomic variation as it relates to human health

The p.Arg408His variant in EYA4 has not been previously reported in individuals with hearing loss, but has been identified in 5/66620 European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Computati onal prediction tools and conservation analysis do not provide strong support fo r or against an impact to the protein. In summary, the clinical significance of the p.Arg408His variant is uncertain.

Variant summary: EYA4 c.1223G>A (p.Arg408His) results in a non-conservative amino acid change located in the EYA domain (IPR006545) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 282562 control chromosomes (gnomAD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in EYA4 causing Dilated Cardiomyopathy (1.6e-05), suggesting that the variant is benign. c.1223G>A has been reported in the literature in at least one individual affected with Left Ventricular Non-Compaction Cardiomyopathy (Miszalski-Jamka_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness 10 (MIM#601316). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (10 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (25 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated haloacid dehalogenase-like hydrolase domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported once as a VUS in ClinVar and also in a patient with left ventricular non-compaction cardiomyopathy (PMID: 28798025). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 408 of the EYA4 protein (p.Arg408His). This variant is present in population databases (rs760787542, gnomAD 0.008%). This missense change has been observed in individual(s) with EYA4-related conditions (PMID: 28798025, 32107406, 32277154). ClinVar contains an entry for this variant (Variation ID: 228680). 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 EYA4 protein function with a negative predictive value of 80%. 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 p.R408H variant (also known as c.1223G>A), located in coding exon 13 of the EYA4 gene, results from a G to A substitution at nucleotide position 1223. The arginine at codon 408 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a left ventricular non-compaction (LVNC) cohort (Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:). This amino acid position is highly conserved in available vertebrate species. 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.