ClinVar Miner

Submissions for variant NM_032119.4(ADGRV1):c.14365C>T (p.Arg4789Trp) (rs1131691924)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493267 SCV000583154 likely pathogenic not provided 2015-08-18 criteria provided, single submitter clinical testing The R4789W variant has been reported previously as a likely pathogenic variant in a cohort of patients diagnosed with Usher syndrome type 2 (Besnard et al. 2012). The R4789W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R4789W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in this residue and in a nearby residue (R4789Q, N4885S) have been reported in the Human Gene Mutation Database in association with Usher syndrome (Stenson et al., 2014). Therefore, based on the currently available information, R4789W is a candidate for a disease-causing variant, although the possibility that it is a benign polymorphism cannot be completely excluded.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000609544 SCV000710878 likely pathogenic Rare genetic deafness 2016-11-19 criteria provided, single submitter clinical testing The p.Arg4789Trp variant in GPR98 has been reported in 1 individual with Usher s yndrome who was compound heterozygous for a second pathogenic variant in GPR98 ( Besnard 2012). This variant was absent from large population studies. Computati onal prediction tools and conservation analyses suggest that this variant may im pact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully est ablish its clinical significance, this variant is likely pathogenic.
Athena Diagnostics Inc RCV000493267 SCV001142922 uncertain significance not provided 2019-07-02 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073322 SCV001238861 likely pathogenic Retinal dystrophy 2018-11-20 criteria provided, single submitter clinical testing
Invitae RCV000493267 SCV001580151 pathogenic not provided 2020-03-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 4789 of the ADGRV1 protein (p.Arg4789Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Usher syndrome (PMID: 22147658, 26969326, Invitae). ClinVar contains an entry for this variant (Variation ID: 430362). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg4789 amino acid residue in ADGRV1. Other variant(s) that disrupt this residue have been observed in individuals with ADGRV1-related conditions (PMID: 23462753), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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