Submissions for variant NM_020366.4(RPGRIP1):c.2367+23del

dbSNP: rs781728563

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004992	SCV001164550	likely pathogenic	Leber congenital amaurosis 6	2018-12-03	criteria provided, single submitter	research	The heterozygous c.2367+23delG variant in RPGRIP1 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with Leber Congenital Amaurosis. The c.2367+23delG variant in RPGRIP1 has not been previously reported in individuals with Leber Congenital Amaurosis but has been identified in 0.02207% (41/185798) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs781728563). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is located in the 5' splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity and a minigene assay in vitro demonstrated abnormal splicing of Intron 15 (PMID: 30072743). In summary, although additional studies are required to fully establish its clinical significance, the c.2367+23delG variant is likely pathogenic. Criteria applied: PM2, PS3 (Richards 2015).
Mendelics	RCV001004992	SCV002519289	uncertain significance	Leber congenital amaurosis 6	2024-02-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469322	SCV002766418	pathogenic	Leber congenital amaurosis	2022-11-21	criteria provided, single submitter	clinical testing	Variant summary: RPGRIP1 c.2367+23delG is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, at least two publications report experimental evidence that this variant affects mRNA splicing (Riera_2017, Jamshidi_2019). The variant allele was found at a frequency of 0.00022 in 160126 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RPGRIP1 causing Leber Congenital Amaurosis (0.00022 vs 0.0011), allowing no conclusion about variant significance. c.2367+23delG has been reported in the literature in individuals affected with Leber Congenital Amaurosis or related disorders (Riera_2017, Yohe_2020, Weisschuh_2020). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324547	SCV004030314	likely pathogenic	Retinitis pigmentosa	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
PreventionGenetics, part of Exact Sciences	RCV003928660	SCV004755968	likely benign	RPGRIP1-related disorder	2019-06-07	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV001004992	SCV001438592	pathogenic	Leber congenital amaurosis 6		no assertion criteria provided	research