ClinVar Miner

Submissions for variant NM_015272.5(RPGRIP1L):c.1843A>C (p.Thr615Pro)

gnomAD frequency: 0.00004  dbSNP: rs121918198
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program, University of Washington RCV000001124 SCV000256469 pathogenic Joubert syndrome 7 2015-02-23 criteria provided, single submitter research
GeneDx RCV000393725 SCV000329909 pathogenic not provided 2022-05-03 criteria provided, single submitter clinical testing Published functional studies demonstrate that T615P significantly disrupts Nephrocystin-4 binding activity (Arts et al., 2007; Delous et al., 2007).; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18565097, 17558407, 17558409, 26092869, 23351400, 21866095, 17960139, 31589614)
Labcorp Genetics (formerly Invitae), Labcorp RCV000689745 SCV000817411 pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome 2024-01-20 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 615 of the RPGRIP1L protein (p.Thr615Pro). This variant is present in population databases (rs121918198, gnomAD 0.01%). This missense change has been observed in individual(s) with cerebello-oculo-renal syndrome (Joubert syndrome type B) (PMID: 17558407, 17558409, 17960139, 18565097, 21866095, 26092869). ClinVar contains an entry for this variant (Variation ID: 1069). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RPGRIP1L protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RPGRIP1L function (PMID: 17558409, 19430481). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002482812 SCV002786156 pathogenic Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3 2022-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155007 SCV003845111 pathogenic Joubert syndrome and related disorders 2023-02-21 criteria provided, single submitter clinical testing Variant summary: RPGRIP1L c.1843A>C (p.Thr615Pro) results in a non-conservative amino acid change located in the C2 domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250524 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RPGRIP1L causing Joubert Syndrome And Related Disorders (6.4e-05 vs 0.00079), allowing no conclusion about variant significance. c.1843A>C has been reported in the literature in multiple individuals affected with Nephronophthisis related ciliopathies. These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000001124 SCV000021274 pathogenic Joubert syndrome 7 2008-08-01 no assertion criteria provided literature only
Natera, Inc. RCV001271279 SCV001452352 pathogenic Familial aplasia of the vermis 2020-09-16 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004528062 SCV004110663 pathogenic RPGRIP1L-related disorder 2024-07-05 no assertion criteria provided clinical testing The RPGRIP1L c.1843A>C variant is predicted to result in the amino acid substitution p.Thr615Pro. This variant has been reported as causative for Joubert syndrome and related disorders (Arts et al. 2007. PubMed ID: 17558407; Delous et al. 2007. PubMed ID: 17558409; Brancati et al. 2008. PubMed ID: 18565097; Chaki et al. 2011.PubMed ID: 21866095; Szymanska et al. 2012. PubMed ID: 23351400). All affected individuals were either homozygous for the c.1843A>C (p.Thr615Pro) variant or compound heterozygous with a nonsense variant. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

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