ClinVar Miner

Submissions for variant NM_020366.3(RPGRIP1):c.2302C>T (p.Arg768Ter) (rs75459701)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000686083 SCV000813586 pathogenic Cone-rod dystrophy 13; Leber congenital amaurosis 6 2017-07-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg768*) in the RPGRIP1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs75459701, ExAC 0.02%). This variant has been reported along with a second variant in an individual affected with Leber congenital amaurosis (PMID: 20079931) and another individual with retinitis pigmentosa (PMID: 26667666). Loss-of-function variants in RPGRIP1 are known to be pathogenic (PMID: 11528500, 23105016, 26766544). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000760501 SCV000890392 pathogenic not provided 2019-01-30 criteria provided, single submitter clinical testing The R768X variant in the RPGRIP1 gene has been reported previously in individuals with Leber congenital amaurosis and retinitis pigmentosa (Walia et al., 2010; Ge et al., 2015). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R768X variant is observed in 6/233980 (0.003%) global alleles in large population cohorts (Lek et al., 2016). We interpret R768X as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000779133 SCV000915638 uncertain significance RPGRIP1L-Related Disorders 2018-08-16 criteria provided, single submitter clinical testing The RPGRIP1 c.2302C>T (p.Arg768Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg768Ter variant has been reported in two individuals from two different studies. A study of patients with Leber congenital amaurosis or early-onset retinitis pigmentosa identified one individual, whose exact phenotype was not described, who carried the p.Arg768Ter variant in a compound heterozygous state with a splice variant (Walia et al. 2010). Another individual with retinitis pigmentosa was found to carry the p.Arg768Ter variant along with two other missense variants, though the phase of these variants is not stated (Ge et al. 2015). Control data are unavailable for this variant, which is found at a frequency of 0.000039 in the Total population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of stop-gained variants, the p.Arg768Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for RPGRIP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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