Submissions for variant NM_032119.4(ADGRV1):c.18754G>A (p.Asp6252Asn)

gnomAD frequency: 0.00016  dbSNP: rs201800819

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000610200	SCV000711066	uncertain significance	not specified	2016-11-17	criteria provided, single submitter	clinical testing	The p.Asp6252Asn variant in GPR98 has not been previously reported in individual s with hearing loss or Usher syndrome. This variant has been identified in seve ral populations by the Exome Aggregation Consortium, including 8/61548 European chromosomes (ExAC, http://exac.broadinstitute.org; dbSNP rs201800819); however, its frequency is not high enough to rule out a pathogenic role. Computational pr ediction tools and conservation analyses do not provide strong support for or ag ainst an impact to the protein. In summary, the clinical significance of this v ariant is uncertain.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756977	SCV000884984	uncertain significance	not provided	2017-09-29	criteria provided, single submitter	clinical testing	The p.Asp6252Asn variant (rs201800819) has not been reported in the medical literature, is absent from ClinVar, and has not been previously identified in our laboratory. The p.Asp6252Asn variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.011% (identified in 31 out of 274,368 chromosomes). The aspartic acid at codon 6,252 is moderately conserved considering 12 species (Alamut software v2.10.0), and computational analyses suggest that this variant does affect the structure/function of the ADGRV1 protein (SIFT: damaging, PolyPhen2: possibly damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the p.Asp6252Asn variant cannot be determined with certainty.
Illumina Laboratory Services, Illumina	RCV001153547	SCV001314842	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000756977	SCV001411368	likely benign	not provided	2025-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000756977	SCV001822542	uncertain significance	not provided	2025-01-08	criteria provided, single submitter	clinical testing	Identified in a patient with autism in published literature; has not been published in association with an ADGRV1-related disorder to our knowledge (PMID: 35982159); In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 35982159)
Fulgent Genetics, Fulgent Genetics	RCV002491231	SCV002780644	uncertain significance	Usher syndrome type 2C; Febrile seizures, familial, 4	2022-03-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002531124	SCV003725035	uncertain significance	Inborn genetic diseases	2021-12-07	criteria provided, single submitter	clinical testing	The c.18754G>A (p.D6252N) alteration is located in exon 89 (coding exon 89) of the ADGRV1 gene. This alteration results from a G to A substitution at nucleotide position 18754, causing the aspartic acid (D) at amino acid position 6252 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004737881	SCV005344340	uncertain significance	ADGRV1-related disorder	2024-09-01	no assertion criteria provided	clinical testing	The ADGRV1 c.18754G>A variant is predicted to result in the amino acid substitution p.Asp6252Asn. To our knowledge, this variant has not been previously reported in association with retinal disease; however, this variant was identified in one individual in a large cohort of individuals with autism (supplementary data, Zhou et al. 2022. PubMed ID: 35982159). This variant is reported in 0.021% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.