ClinVar

Description

The p.Arg3147Gln variant in ADGRV1 (also known as GPR98) has been previously reported in 5 individuals with hearing loss (Neveling 2013, LMM data), 4 of whom also carried the p.Gly573Val variant of uncertain significance in ADGRV1. These two variants were determined to be in cis in 1 individual tested at our laboratory. The p.Arg3147Gln variant has also been reported in ClinVar (Variation ID # 46404) as of uncertain significance. It has also been identified in 0.1% (42/35316) of Latino chromosomes at a similar frequency as the p.Gly573Val variant (0.1%; 41/35348 Latino chromosomes) by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200792658 and dbSNP rs200789563). Collectively, these data suggest that these variants are in linkage disequilibrium and are in cis in all reported individuals identified thus far. Moreover, arginine (Arg) at position 3147 is not conserved in mammals or evolutionarily distant species. Of note, 2 mammals (Elephant and Opossum) carry a glutamine (Gln) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg3147Gln variant is uncertain. ACMG/AMP criteria applied: BS1_Supporting, BP4.