Submissions for variant NM_032119.4(ADGRV1):c.1718G>T (p.Gly573Val)

gnomAD frequency: 0.00036  dbSNP: rs200789563

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039546	SCV000063235	uncertain significance	not specified	2020-06-04	criteria provided, single submitter	clinical testing	The p.Gly573Val variant in ADGRV1 has been previously reported in 4 individuals with hearing loss (Neveling 2013, LMM data), all of whom also carried the p.Arg3147Gln variant of unknown significance in GPR98. These two variants were determined to be in cis in 1 individual tested at our laboratory. The p.Gly573Val variant has also been reported in ClinVar (Variation ID # 46290) as of uncertain significance. The p.Gly573Val variant has been identified in 0.1% (41/35348) of Latino chromosomes at a similar frequency of the p.Arg3147Gln variant at 0.1% (42/35316) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200789563 and rs200792658). All information collectively suggests that these variants are in linkage disequilibrium and are likely in cis in all of the reported individuals. Although the p.Gly753Val variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Additionally, computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: BS1_Supporting.
Eurofins Ntd Llc (ga)	RCV000513285	SCV000340753	uncertain significance	not provided	2017-11-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513285	SCV000609166	uncertain significance	not provided	2017-04-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000513285	SCV001235005	likely benign	not provided	2025-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001152886	SCV001314124	uncertain significance	Usher syndrome type 2C	2017-04-28	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV004527308	SCV005038689	uncertain significance	Febrile seizures, familial, 4		criteria provided, single submitter	not provided
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039546	SCV005381130	uncertain significance	not specified	2024-08-14	criteria provided, single submitter	clinical testing	Variant summary: ADGRV1 c.1718G>T (p.Gly573Val) 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 249058 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.1718G>T has been reported in the literature in individuals affected with Usher Syndrome, progressive hearing loss and epilepsy, often reported in cis with c.9440G>A (p.Arg3147Gln) (Neveling_2013, Sharon_2020, Dahawi_2021, Zhou_2022). 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, 35813073). ClinVar contains an entry for this variant (Variation ID: 46290). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002855	SCV001160882	likely pathogenic	Usher syndrome type 2	2019-06-23	no assertion criteria provided	research
Paris Brain Institute, Inserm - ICM	RCV001839409	SCV001810135	likely pathogenic	Idiopathic generalized epilepsy		no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000513285	SCV001959105	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513285	SCV001970305	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004724764	SCV005335461	uncertain significance	ADGRV1-related disorder	2024-08-15	no assertion criteria provided	clinical testing	The ADGRV1 c.1718G>T variant is predicted to result in the amino acid substitution p.Gly573Val. This variant was reported along with a second missense variant (c.9440G>A, p.Arg3147Gln) 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.