Submissions for variant NM_032119.4(ADGRV1):c.8161A>G (p.Ile2721Val) (rs201963060)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000039642	SCV000063331	likely benign	not specified	2012-04-17	criteria provided, single submitter	clinical testing	p.Ile2721Val in exon 35 of GPR98: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. In addition, computational prediction tools do not suggest a high likelihood of im pact to the protein. It has been identified in 0.13% (60/38684) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs201963060).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000724489	SCV000229799	uncertain significance	not provided	2015-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000724489	SCV000978896	likely benign	not provided	2018-06-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000724489	SCV001210534	uncertain significance	not provided	2020-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with valine at codon 2721 of the ADGRV1 protein (p.Ile2721Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs201963060, ExAC 0.1%). This variant has not been reported in the literature in individuals with ADGRV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 46386). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina	RCV001151661	SCV001312826	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.