ClinVar Miner

Submissions for variant NM_032119.4(ADGRV1):c.14973-2A>G (rs371981035)

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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 RCV000039531 SCV000063220 pathogenic Rare genetic deafness 2020-07-03 criteria provided, single submitter clinical testing The c.14973-2A>G variant in ADGRV1 has been reported in 1 individual with Usher syndrome who harbored a second variant in ADGRV1 and segregated with disease in 1 affected relative (LMM internal data). It has also been identified in 0.16% (12/7704) of Ashkenazi Jewish chromosomes and 1/84474 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID: 46275). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal 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, PP1, PP4
Invitae RCV001041197 SCV001204799 likely pathogenic not provided 2020-07-08 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 73 of the ADGRV1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs371981035, ExAC 0.03%). This variant has not been reported in the literature in individuals with ADGRV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 46275). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ADGRV1 are known to be pathogenic (PMID: 19357117, 22135276, 22147658). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics RCV001073981 SCV001239547 likely pathogenic Retinal dystrophy 2018-09-04 criteria provided, single submitter clinical testing
Sharon lab,Hadassah-Hebrew University Medical Center RCV001002859 SCV001160886 pathogenic Usher syndrome type 2 2019-06-23 no assertion criteria provided research

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