ClinVar Miner

Submissions for variant NM_015272.5(RPGRIP1L):c.466C>T (p.Arg156Cys)

gnomAD frequency: 0.00006  dbSNP: rs527539036
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001070731 SCV001235999 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome 2022-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the RPGRIP1L protein (p.Arg156Cys). This variant is present in population databases (rs527539036, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with RPGRIP1L-related conditions. ClinVar contains an entry for this variant (Variation ID: 863702). 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 expected to disrupt RPGRIP1L protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002480439 SCV002787831 uncertain significance Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3 2024-03-04 criteria provided, single submitter clinical testing
GeneDx RCV003320803 SCV004025597 uncertain significance not provided 2023-07-31 criteria provided, single submitter clinical testing Identified as heterozygous with another RPGRIP1L variant on the same allele (in cis) in a patient with Meckel-Gruber syndrome (Szymanska et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 23351400)
Natera, Inc. RCV001273841 SCV001457426 uncertain significance Familial aplasia of the vermis 2020-09-16 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004536135 SCV004710534 uncertain significance RPGRIP1L-related disorder 2024-07-17 no assertion criteria provided clinical testing The RPGRIP1L c.466C>T variant is predicted to result in the amino acid substitution p.Arg156Cys. This variant was reported in the heterozygous state without a second potentially causative variant in two patients with features of Meckel syndrome consisting of occipital encephalocele and polycystic kidneys (Szymanska et al. 2012. PubMed ID: 23351400). This variant is reported in 0.14% of alleles in individuals of South Asian descent in gnomAD, which is higher than expected for a pathogenic variant in this gene. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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