ClinVar Miner

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

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Total submissions: 7
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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; 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 2018-10-01 criteria provided, single submitter clinical testing The Q2301X nonsense variant has been reported previously in association with Usher syndrome (Weston et al., 2004; Schwartz et al., 2005; Sujirakul et al., 2015). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We consider this variant to be pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763550 SCV000894367 pathogenic Usher syndrome, type 2C; Febrile seizures, familial, 4 2018-10-31 criteria provided, single submitter clinical testing
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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