Submissions for variant NM_015272.5(RPGRIP1L):c.2614C>T (p.Gln872Ter)

gnomAD frequency: 0.00005  dbSNP: rs121918203

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790748	SCV000226652	pathogenic	not provided	2013-09-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762961	SCV000893402	likely pathogenic	COACH syndrome 1; Joubert syndrome 7; Meckel syndrome, type 5	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779628	SCV000914250	uncertain significance	RPGRIP1L-related disorder	2019-04-08	criteria provided, single submitter	clinical testing	The RPGRIP1L c.2614C>T (p.Gln872Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Gln872Ter variant has been reported in one study in which it was found in a compound heterozygous state with a second stop-gained variant in a fetus diagnosed with Meckel syndrome (Delous et al. 2007). Control data are unavailable for this variant, which is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence and the potential impact of stop-gained variants, the p.Gln872Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for RPGRIP1L -related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059320	SCV001223942	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln872*) in the RPGRIP1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPGRIP1L are known to be pathogenic (PMID: 17558409). This variant is present in population databases (rs121918203, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Meckel syndrome (PMID: 17558409). ClinVar contains an entry for this variant (Variation ID: 1074). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017218	SCV004848431	likely pathogenic	Meckel-Gruber syndrome	2020-08-11	criteria provided, single submitter	clinical testing	The p.Gln872X variant in RPGRIP1L has been reported in one French individual with Meckel Syndrome, who also carried a second variant (p.Q345X) in the same gene (Delous 2007 PMID: 17558509). This variant has also been reported in ClinVar (Variation ID 1074) and identified in 0.00004% (5/113470) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 872, which is predicted to lead to a truncated or absent protein. Please note, the exon it resides in (exon 17) is alternatively spliced out of two of seven ubiquitously expressed transcripts. Complete loss of RPGRIP1L function is an established disease mechanism in RPGRIP1L-related disorders such as Joubert syndrome and Meckel syndrome (Delous 2007). Moreover, Rpgrip1l -/- mice show a similar phenotype to individuals affected with these disorders including polydactyly, craniofacial malformations, and left-right symmetry defects (Vierkotten 2007). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive RPGRIP1L-related disorders. ACMG/AMP criteria applied: PVS1_Strong, PM2, PM3.
OMIM	RCV000033207	SCV000057053	pathogenic	Meckel syndrome, type 5	2007-07-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001831501	SCV002085692	pathogenic	Familial aplasia of the vermis	2021-08-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000779628	SCV004708494	pathogenic	RPGRIP1L-related disorder	2024-01-30	no assertion criteria provided	clinical testing	The RPGRIP1L c.2614C>T variant is predicted to result in premature protein termination (p.Gln872*). This variant has been reported together with another truncating variant in a fetus with phenotypic features consistent with Meckel-Gruber syndrome (Delous et al. 2007. PubMed ID: 17558409). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in RPGRIP1L are expected to be pathogenic. This variant is interpreted as pathogenic.