Submissions for variant NM_032119.4(ADGRV1):c.9877C>T (p.Arg3293Ter)

dbSNP: rs769215629

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000602394	SCV000731681	pathogenic	Rare genetic deafness	2017-07-10	criteria provided, single submitter	clinical testing	The p.Arg3293X variant in GPR98 has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 1/109096 Europea n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org/; dbSNP rs769215629). This nonsense variant leads to a premature term ination codon at position 3293, which is predicted to lead to a truncated or abs ent protein. Loss of function of the GPR98 gene is an established disease mechan ism in autosomal recessive Usher syndrome type 2. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome type 2 in an autosom al recessive manner based on predicted impact to the protein.
Blueprint Genetics	RCV001073335	SCV001238875	likely pathogenic	Retinal dystrophy	2018-12-05	criteria provided, single submitter	clinical testing
Invitae	RCV001382658	SCV001581550	pathogenic	not provided	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg3293*) in the ADGRV1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADGRV1 are known to be pathogenic (PMID: 19357117, 22135276, 22147658, 26226137, 30718709, 31047384, 32467589). This variant is present in population databases (rs769215629, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of Usher syndrome (PMID: 27460420). ClinVar contains an entry for this variant (Variation ID: 517415). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
DASA	RCV002221563	SCV002499406	pathogenic	Usher syndrome type 2C	2022-04-10	criteria provided, single submitter	clinical testing	The c.9877C>T;p.(Arg3293*) variant creates a premature translational stop signal in the ADGRV1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 517415; PMID: 27460420) - PS4. The variant is present at low allele frequencies population databases (rs769215629 – gnomAD 0.00008302%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg3293*) was detected in trans with a pathogenic variant (PMID: 27460420) - PM3_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
GeneDx	RCV001382658	SCV002569779	pathogenic	not provided	2022-08-23	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32037395, 27460420)