ClinVar Miner

Submissions for variant NM_032119.4(ADGRV1):c.12798T>A (p.Tyr4266Ter) (rs777309662)

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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 RCV000504819 SCV000712269 pathogenic Usher syndrome 2019-10-10 criteria provided, single submitter clinical testing The p.Tyr4266X variant in ADGRV1 (also known as GPR98) has been previously reported in two individuals with hearing loss by our laboratory. Both individuals were tested before the age of 5 years and were not reported to have any vision concerns. This variant has also been identified in 0.02% (6/30350) South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 4266, which is predicted to lead to a truncated or absent protein. Loss of function of the ADGRV1 gene is an established disease mechanism in autosomal recessive Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PVS1, PM3_Supporting, PP1, PM2_Supporting.
Blueprint Genetics RCV001075449 SCV001241072 pathogenic Retinal dystrophy 2018-09-21 criteria provided, single submitter clinical testing
Invitae RCV001381661 SCV001580150 pathogenic not provided 2020-09-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr4266*) in the ADGRV1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs777309662, ExAC 0.02%). This variant has been observed in individual(s) with Usher syndrome (PMID: 28041643). ClinVar contains an entry for this variant (Variation ID: 438168). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in ADGRV1 are known to be pathogenic (PMID: 19357117, 22135276, 22147658). For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504819 SCV000599107 likely pathogenic Usher syndrome 2015-01-01 no assertion criteria provided research

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