ClinVar Miner

Submissions for variant NM_032119.4(ADGRV1):c.6901C>T (p.Gln2301Ter) (rs121909762)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000007200 SCV000459098 likely pathogenic Usher syndrome, type 2C 2016-09-19 criteria provided, single submitter clinical testing The ADGRV1 c.6901C>T (p.Gln2301Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The variant was first reported by Weston et al. (2004) in a total of six individuals with Usher syndrome, including four siblings (including a pair of identical twins) who were homozygous for the variant, a sporadic case from a consanguineous family who was homozygous, and a sporadic case who was heterozygous with a second unidentified variant. The p.Gln2301Ter variant was also identified in a heterozygous state in the unaffected father of the siblings. Sujirakul et al. (2015) identified an individual with autosomal recessive retinitis pigmentosa who carried the p.Gln2301Ter variant and a second heterozygous variant, though the phase of the variants is unclear. Schuerch et al. (2016) found the p.Gln2301Ter variant in a homozygous state in an individual with an unspecified phenotype. The p.Gln2301Ter variant was absent from 190 control chromosomes (Weston et al. 2004), but is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and evidence from the literature, the p.Gln2301Ter variant is classified as likely pathogenic for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727026 SCV000705015 pathogenic not provided 2017-01-25 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844603 SCV000710853 pathogenic Rare genetic deafness 2017-12-14 criteria provided, single submitter clinical testing The p.Gln2301X variant in ADGRV1 has been reported in the homozygous or compound heterozygous state with another loss-of-function variant in 3 individuals with Usher syndrome and segregated with disease in 2 affected relatives from 1 family (Weston 2004, Sujirakul 2015). This variant has been identified in 14/276946 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs121909762). It has also been reported in ClinVar (Varia tion ID: 6798). Although this variant has been seen in the general population, i ts frequency is low enough to be consistent with a recessive carrier frequency f or Usher syndrome. This nonsense variant leads to a premature termination codon at position 2301, which is predicted to lead to a truncated or absent protein. L oss of function of the ADGRV1 gene is an established disease mechanism in autoso mal recessive Usher syndrome type 2. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based upon predicted impact to the protein and the identification of the variant in homozygosity or compound heterozygosity in affected individuals. ACMG/AMP Cr iteria applied: PVS1; PM3_Strong.
GeneDx RCV000727026 SCV000890167 pathogenic not provided 2020-11-18 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; This variant is associated with the following publications: (PMID: 23891399, 25525159, 14740321, 18463160, 26164827, 28041643, 15671307, 32581362)
Fulgent Genetics,Fulgent Genetics RCV000763550 SCV000894367 pathogenic Usher syndrome, type 2C; Febrile seizures, familial, 4 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000727026 SCV001578460 pathogenic not provided 2020-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln2301*) in the ADGRV1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121909762, ExAC 0.004%). This variant has been observed in individual(s) with ADGRV1-related conditions (PMID: 14740321, 26164827). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6798). 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.
OMIM RCV000007200 SCV000027396 pathogenic Usher syndrome, type 2C 2004-02-01 no assertion criteria provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505021 SCV000599111 pathogenic Usher syndrome 2015-01-01 no assertion criteria provided research

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