Submissions for variant NM_032119.4(ADGRV1):c.746G>A (p.Arg249Lys)

gnomAD frequency: 0.00668  dbSNP: rs41303344

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039630	SCV000063319	benign	not specified	2012-03-26	criteria provided, single submitter	clinical testing	Arg249Lys in exon 7 of GPR98: This variant is not expected to have clinical sign ificance because it has been identified in 1.17% (77/6554) of European American chromosomes and 0.17% (5/2954) of African American chromosomes in a broad popula tion by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; d bSNP rs41303344).
GeneDx	RCV000430094	SCV000168738	benign	not provided	2018-12-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28041643, 32581362)
Eurofins Ntd Llc (ga)	RCV000039630	SCV000344963	benign	not specified	2016-09-19	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000430094	SCV000511515	likely benign	not provided	2016-06-21	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Athena Diagnostics Inc	RCV000430094	SCV000840684	benign	not provided	2018-01-19	criteria provided, single submitter	clinical testing
Invitae	RCV000430094	SCV001117314	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000430094	SCV001156559	likely benign	not provided	2023-08-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001154055	SCV001315375	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039630	SCV003844949	likely benign	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: ADGRV1 c.746G>A (p.Arg249Lys) results in a conservative amino acid change in 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 0.0064 in 247404 control chromosomes, predominantly at a frequency of 0.0096 within the Non-Finnish European subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.78 fold of the estimated maximal expected allele frequency for a pathogenic variant in ADGRV1 causing Usher Syndrome phenotype (0.0054), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.746G>A has been reported in the literature in one individual affected with Inherited Retinal Disease (Carss_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=1), Benign (n=4), Likely Benign (n=2) and Likely Pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000430094	SCV004011605	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ADGRV1: BP4, BS1, BS2
Genetic Services Laboratory, University of Chicago	RCV000039630	SCV000193288	likely benign	not specified		no assertion criteria provided	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504660	SCV000599112	likely pathogenic	Usher syndrome	2015-01-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000039630	SCV001919459	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000430094	SCV001931747	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000430094	SCV001973728	likely benign	not provided		no assertion criteria provided	clinical testing