Submissions for variant NM_032119.4(ADGRV1):c.12212G>A (p.Arg4071Gln)

gnomAD frequency: 0.00074  dbSNP: rs202190568

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155112	SCV000204798	likely benign	not specified	2016-10-06	criteria provided, single submitter	clinical testing	p.Arg4071Gln in exon 59 of GPR98: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, more than 10 different mammals have a glutamine (Gln) at this position despite high nearby amino acid conservation. In addition, this variant was iden tified in 0.1% (74/66372) of European chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs202190568).
Eurofins Ntd Llc (ga)	RCV000514796	SCV000231444	uncertain significance	not provided	2014-08-22	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514796	SCV000610693	uncertain significance	not provided	2017-10-04	criteria provided, single submitter	clinical testing
Invitae	RCV000514796	SCV001059455	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514796	SCV001154445	uncertain significance	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001155715	SCV001317170	uncertain significance	Usher syndrome type 2C	2018-01-12	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000514796	SCV001764659	likely benign	not provided	2019-08-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155112	SCV002766482	uncertain significance	not specified	2022-11-09	criteria provided, single submitter	clinical testing	Variant summary: ADGRV1 c.12212G>A (p.Arg4071Gln) results in a conservative amino acid change located in the Na-Ca exchanger/integrin-beta4 domain (IPR003644) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 249010 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ADGRV1 causing Usher Syndrome (0.00072 vs 0.0054), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.12212G>A in individuals affected with features of ADGRV1-Related Disorders such as Usher Syndrome type 2C or Familial Febrile Seizures 4 and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; Likely Benign, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.