ClinVar Miner

Submissions for variant NM_032119.4(ADGRV1):c.1180del (p.Ser394fs) (rs1400695342)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825554 SCV000966872 pathogenic Rare genetic deafness 2018-04-05 criteria provided, single submitter clinical testing The p.Ser394fs variant in ADGRV1 has not been previously reported in individuals with Usher syndrome. This variant was present in 2/108680 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org); h owever, its frequency is low enough to be consistent with a recessive carrier fr equency. This variant is predicted to cause a frameshift, which alters the prote in?s amino acid sequence beginning at position 394 and leads to a premature term ination codon 12 amino acids downstream. This alteration is then predicted to le ad to a truncated or absent protein. Loss of function of the ADGRV1 gene is an e stablished disease mechanism for Usher syndrome. Furthermore, the presence of th is variant in trans with a pathogenic variant in an individual with hearing loss supports pathogenicity for the p.Ser394fs variant. In summary, this variant mee ts criteria to be classified as pathogenic for autosomal recessive Usher syndrom e based upon the predicted impact of the variant, low frequency in the general p opulation and presence in trans with a pathogenic variant. ACMG/AMP Criteria app lied: PVS1, PM2, PM3.
GeneDx RCV001008515 SCV001168287 likely pathogenic not provided 2019-01-22 criteria provided, single submitter clinical testing The c.1180delT variant in causes a frameshift starting with codon Serine 394, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Ser394HisfsX12. This likely pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.1180delT variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. In summary, we interpret this variant as likely pathogenic.

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