ClinVar Miner

Submissions for variant NM_032119.4(ADGRV1):c.18754G>A (p.Asp6252Asn) (rs201800819)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 Clinical Services Laboratory,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.
Invitae RCV000756977 SCV001411368 uncertain significance not provided 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 6252 of the ADGRV1 protein (p.Asp6252Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs201800819, ExAC 0.02%). This variant has not been reported in the literature in individuals with ADGRV1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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