Submissions for variant NM_015272.5(RPGRIP1L):c.2200C>T (p.Arg734Ter)

gnomAD frequency: 0.00004  dbSNP: rs751128300

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484741	SCV000570956	pathogenic	not provided	2023-10-16	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31964843)
Invitae	RCV000697158	SCV000825754	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg734*) 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 (rs751128300, gnomAD 0.005%). 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: 421673). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509406	SCV002819834	likely pathogenic	Joubert syndrome and related disorders	2022-12-04	criteria provided, single submitter	clinical testing	Variant summary: RPGRIP1L c.2200C>T (p.Arg734X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 251404 control chromosomes. To our knowledge, no occurrence of c.2200C>T in individuals affected with Joubert Syndrome And Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two 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 likely pathogenic.
Ambry Genetics	RCV002526604	SCV003548506	pathogenic	Inborn genetic diseases	2020-11-04	criteria provided, single submitter	clinical testing	The c.2200C>T (p.R734*) alteration, located in exon 16 (coding exon 15) of the RPGRIP1L gene, consists of a C to T substitution at nucleotide position 2200. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 734. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the available evidence, this alteration is classified as pathogenic.