Submissions for variant NM_032119.4(ADGRV1):c.18001A>T (p.Met6001Leu) (rs200530343)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000615485	SCV000711064	uncertain significance	not specified	2016-11-17	criteria provided, single submitter	clinical testing	The p.Met6001Leu variant in GPR98 has not been previously reported in individual s with hearing loss or Usher syndrome. This variant has been identified in 7/61 554 European and 2/9336 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200530343); however, its frequenc y is not high enough to rule out a pathogenic role. Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. In summary, the clinical significance of the p.Met6001Leu va riant is uncertain.
Illumina Clinical Services Laboratory,Illumina	RCV001156037	SCV001317513	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.
Invitae	RCV001238549	SCV001411367	uncertain significance	not provided	2019-08-08	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with leucine at codon 6001 of the ADGRV1 protein (p.Met6001Leu). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs200530343, ExAC 0.02%). This variant has not been reported in the literature in individuals with ADGRV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 504588). 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.

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