Submissions for variant NM_020366.4(RPGRIP1):c.2302C>T (p.Arg768Ter)

gnomAD frequency: 0.00004  dbSNP: rs75459701

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000686083	SCV000813586	pathogenic	Cone-rod dystrophy 13; Leber congenital amaurosis 6	2023-10-13	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. Loss-of-function variants in RPGRIP1 are known to be pathogenic (PMID: 11528500, 23105016). This variant is present in population databases (rs75459701, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Leber congenital amaurosis or retinitis pigmentosa (PMID: 20079931). ClinVar contains an entry for this variant (Variation ID: 566311). 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.
GeneDx	RCV000760501	SCV000890392	pathogenic	not provided	2020-10-26	criteria provided, single submitter	clinical testing	Reported with a second variant in multiple individuals diagnosed with retinitis pigmentosa or Leber congenital amaurosis in the published literature (Walia et al, 2010; Ge et al., 2015); 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: 20079931, 26667666, 30072743, 32165824, 31589614)
Illumina Laboratory Services, Illumina	RCV000779133	SCV000915638	uncertain significance	RPGRIP1L-related disorder	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.
Genome-Nilou Lab	RCV001800848	SCV002045956	pathogenic	Leber congenital amaurosis 6	2021-11-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001800849	SCV002045967	pathogenic	Cone-rod dystrophy 13	2021-11-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003403585	SCV004120027	pathogenic	RPGRIP1-related disorder	2023-05-26	criteria provided, single submitter	clinical testing	The RPGRIP1 c.2302C>T variant is predicted to result in premature protein termination (p.Arg768*). This variant has previously been reported to be causative for Leber congenital amaurosis (Walia et al 2010. PubMed ID: 20079931; Ge Z et al 2015. PubMed ID: 26667666; Jamshidi F et al 2018. PubMed ID: 30072743; Zhu L et al 2021. PubMed ID: 33970760). This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-21793477-C-T). Nonsense variants in RPGRIP1 are expected to be pathogenic. This variant is interpreted as pathogenic.