ClinVar Miner

Submissions for variant NM_020366.4(RPGRIP1):c.1468-2A>G

gnomAD frequency: 0.00004  dbSNP: rs751342895
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000592649 SCV000703462 pathogenic not provided 2016-12-09 criteria provided, single submitter clinical testing
Invitae RCV001854022 SCV002241998 pathogenic Cone-rod dystrophy 13; Leber congenital amaurosis 6 2023-07-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 11 of the RPGRIP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RPGRIP1 are known to be pathogenic (PMID: 11528500, 23105016). This variant is present in population databases (rs751342895, gnomAD 0.05%). Disruption of this splice site has been observed in individuals with inherited retinal dystrophy (PMID: 21602930, 28456785, 31630094). ClinVar contains an entry for this variant (Variation ID: 498452). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282254 SCV002570916 pathogenic Leber congenital amaurosis 2022-07-14 criteria provided, single submitter clinical testing Variant summary: RPGRIP1 c.1468-2A>G is located in a canonical splice-site in intron 11 and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. These predictions have been confirmed by sequencing evidence which has shown that the variant results in the complete loss of exon 12, causing the removal of 48 amino acids from the protein as a result of mis-splicing (Huang_2017). The variant allele was found at a frequency of 4e-05 in 247222 control chromosomes, exclusively within the East Asian subpopulation (at a frequency of 0.00056) in the gnomAD database. This frequency is not higher than estimated for a pathogenic variant in RPGRIP1 causing Leber Congenital Amaurosis (4e-05 vs 0.0011). c.1468-2A>G has been reported in the literature in the compound heterozygous state in individuals affected with Leber Congenital Amaurosis and in a homozygous individual affected with retinitis pigmentosa (e.g. Li_2011, Huang_2017, Xu_2020). These data indicate that the variant is likely associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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