ClinVar Miner

Submissions for variant NM_015272.5(RPGRIP1L):c.1843A>C (p.Thr615Pro) (rs121918198)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000393725 SCV000329909 pathogenic not provided 2016-04-06 criteria provided, single submitter clinical testing The T615P pathogenic variant in the RPGRIP1L gene has been reported previously in the homozygous state or in trans with another pathogenic RPGRIP1L variant in multiple individuals with Joubert syndrome and related disorders (Arts et al., 2007; Delous et al., 2007; Brancati et al., 2008). The T615P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the T615P missense substitution occurs at a position that is not conserved, the T615P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In vitro studies indicate that T615P significantly disrupts Nephrocystin-4 binding activity (Arts et al., 2007; Delous et al., 2007). We interpret T615P as a pathogenic variant.
Invitae RCV000689745 SCV000817411 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2018-08-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 615 of the RPGRIP1L protein (p.Thr615Pro). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and proline. This variant is present in population databases (rs121918198, ExAC 0.009%). This variant has been observed to be homozygous and in combination with another RPGRIP1L variant in individuals with cerebello-oculo-renal syndrome (Joubert syndrome type B) (PMID: 17558407, 17558409, 21866095, 18565097, 17960139, 26092869). ClinVar contains an entry for this variant (Variation ID: 1069). Experimental studies have shown used that this missense change causes a reduction in RPGRIP1L protein binding to nephrocystin-4 (PMID: 17558409).  Additionally, this variant failed to rescue the mutant phenotype in zebrafish morpholino experiments (PMID: 19430481). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001124 SCV000021274 pathogenic Joubert syndrome 7 2008-08-01 no assertion criteria provided literature only
UW Hindbrain Malformation Research Program,University of Washington RCV000001124 SCV000256469 pathogenic Joubert syndrome 7 2015-02-23 criteria provided, single submitter research

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