ClinVar Miner

Submissions for variant NM_032119.4(ADGRV1):c.13358A>G (p.His4453Arg) (rs200212083)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000490059 SCV000577348 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing The H4453R variant in the ADGRV1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The H4453R variant is observed in 43/126528 (0.034%) alleles from individuals of non-Finnish background, in large population cohorts (Lek et al., 2016). The H4453R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret H4453R as a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000765854 SCV000897250 uncertain significance Usher syndrome, type 2C; Febrile seizures, familial, 4 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000490059 SCV001225149 uncertain significance not provided 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 4453 of the ADGRV1 protein (p.His4453Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs200212083, ExAC 0.02%). This variant has been observed in individual(s) with Usher syndrome (PMID: 22135276). ClinVar contains an entry for this variant (Variation ID: 426807). 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: "Tolerated"; 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195219 SCV001365526 uncertain significance not specified 2019-06-21 criteria provided, single submitter clinical testing The p.His4453Arg variant in ADGRV1 has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 0.03% (48/128280) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 426807). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting.

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