Submissions for variant NM_020366.4(RPGRIP1):c.1792C>T (p.Arg598Ter)

gnomAD frequency: 0.00002  dbSNP: rs775935766

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578972	SCV000681155	likely pathogenic	not provided	2017-11-28	criteria provided, single submitter	clinical testing	The R598X variant in the RPGRIP1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R598X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R598X as a likely pathogenic variant.
Invitae	RCV001238568	SCV001411388	pathogenic	Cone-rod dystrophy 13; Leber congenital amaurosis 6	2023-01-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 489168). This variant has not been reported in the literature in individuals affected with RPGRIP1-related conditions. This variant is present in population databases (rs775935766, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg598*) in the RPGRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPGRIP1 are known to be pathogenic (PMID: 11528500, 23105016).
Genome-Nilou Lab	RCV001800794	SCV002045900	likely pathogenic	Leber congenital amaurosis 6	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226328	SCV003923146	likely pathogenic	Leber congenital amaurosis	2023-03-03	criteria provided, single submitter	clinical testing	Variant summary: RPGRIP1 c.1792C>T (p.Arg598X) 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 6e-05 in 249040 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RPGRIP1 causing Leber Congenital Amaurosis (6e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1792C>T in individuals affected with Leber Congenital Amaurosis and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1)/likely pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003420017	SCV004107160	likely pathogenic	RPGRIP1-related disorder	2023-06-27	criteria provided, single submitter	clinical testing	The RPGRIP1 c.1792C>T variant is predicted to result in premature protein termination (p.Arg598*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-21792806-C-T). Nonsense variants in RPGRIP1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.