ClinVar Genomic variation as it relates to human health

Variant summary: ADGRV1 c.9440G>A (p.Arg3147Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 248466 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ADGRV1 causing Usher Syndrome (0.0003 vs 0.0054), allowing no conclusion about variant significance. c.9440G>A has been reported in the literature in individuals affected with Usher Syndrome, progressive hearing loss and epilepsy, often reported in cis with c.1718G>T (p.Gly573Val) (Neveling_2013, Sharon_2020, Dahawi_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34744978, 24123792, 31456290). ClinVar contains an entry for this variant (Variation ID: 46290). Based on the evidence outlined above, the variant was classified as uncertain significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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.

The ADGRV1 c.9440G>A variant is predicted to result in the amino acid substitution p.Arg3147Gln. This variant was reported along with a second missense variant (c.1718G>T, p.Gly573Val) in three siblings with progressive hearing loss with unreported phase (Neveling et al. 2013. PubMed ID: 24123792), in a cohort of patients with inherited retinal disease (Table S2, Sharon et al. 2019. PubMed ID: 31456290), and in cis phase in one individual with epilepsy (Dahawi et al. 2021. PubMed ID: 34744978). Based on internal data, the c.1718G>T and c.9440G>A variants are frequently detected together, suggesting that they are often found in cis. This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.