Submissions for variant NM_015272.5(RPGRIP1L):c.3529C>T (p.Arg1177Ter)

gnomAD frequency: 0.00002  dbSNP: rs778533826

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201661	SCV000256467	pathogenic	Joubert syndrome 7	2015-02-23	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853237	SCV002229404	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1177*) 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 (rs778533826, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of Joubert syndrome (PMID: 26092869). ClinVar contains an entry for this variant (Variation ID: 217694). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002492927	SCV002800733	pathogenic	Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3	2022-04-24	criteria provided, single submitter	clinical testing
GeneDx	RCV002509297	SCV002818854	pathogenic	not provided	2022-07-08	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: 26092869)
Ambry Genetics	RCV002517313	SCV003722023	pathogenic	Inborn genetic diseases	2022-07-21	criteria provided, single submitter	clinical testing	The c.3529C>T (p.R1177*) alteration, located in exon 24 (coding exon 23) of the RPGRIP1L gene, consists of a C to T substitution at nucleotide position 3529. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 1177. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (4/251476) total alleles studied. The highest observed frequency was <0.01% (1/30616) of South Asian alleles. This variant was identified in one individual with Joubert syndrome in conjunction with a second RPGRIP1L variant (Bachmann-Gagescu, 2015). Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004732786	SCV005357412	likely pathogenic	RPGRIP1L-related disorder	2024-08-06	no assertion criteria provided	clinical testing	The RPGRIP1L c.3529C>T variant is predicted to result in premature protein termination (p.Arg1177*). This variant was reported in conjunction with a second RPGRIP1L variant in an individual with Joubert syndrome (Table S5. Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). This variant was also identified in individuals with Meckel syndrome (Table S3. Hanany et al. 2020. PubMed ID: 31964843). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in RPGRIP1L are expected to be pathogenic. This variant is interpreted as likely pathogenic.