ClinVar Miner

Submissions for variant NM_020366.4(RPGRIP1):c.2895+1G>T

gnomAD frequency: 0.00001  dbSNP: rs748072501
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001880011 SCV002208945 pathogenic Cone-rod dystrophy 13; Leber congenital amaurosis 6 2024-04-23 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 17 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 (rs748072501, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with Leber congenital amaurosis (PMID: 33670832; Invitae). ClinVar contains an entry for this variant (Variation ID: 981634). 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.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel RCV003324559 SCV004030315 pathogenic Leber congenital amaurosis 2023-07-24 criteria provided, single submitter research Clinical significance based on ACMG v2.0
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003324559 SCV005886533 pathogenic Leber congenital amaurosis 2025-02-13 criteria provided, single submitter clinical testing Variant summary: RPGRIP1 c.2895+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of RPGRIP1 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. One predicts the variant abolishes a cryptic 5' donor site. Two predict the variant strengthens a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.8e-06 in 227304 control chromosomes. c.2895+1G>T has been reported in the presumed compound heterozygous state in the literature and internally in multiple individuals affected with Leber Congenital Amaurosis (example, Panneman_2023, Perrault_2021, Peter_2023, Labcorp Genetics (formerly Invitae)). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36819107, 33670832, 36909829). ClinVar contains an entry for this variant (Variation ID: 981634). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV001261174 SCV001438570 pathogenic Leber congenital amaurosis 6 no assertion criteria provided research

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