Submissions for variant NM_020366.4(RPGRIP1):c.2668C>T (p.Arg890Ter)

dbSNP: rs780587095

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000298896	SCV000329893	pathogenic	not provided	2017-10-30	criteria provided, single submitter	clinical testing	The R890X pathogenic variant in the RPGRIP1 gene has been reported previously in association with Leber congenital amaurosis when present in the homozygous state or when in trans with another pathogenic variant (Gerber et al., 2001; Hanein et al., 2004; Galvin et al., 2005). Yeast two-hybrid screening and coimmunopreciptation assays showed that the R890X variant severely disrupts the interaction of RPGRIP1 with nephrocystin-4 compared to wild type (Roepman et al., 2005). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R890X variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R890X as a pathogenic variant.
Invitae	RCV002518810	SCV003442778	pathogenic	Cone-rod dystrophy 13; Leber congenital amaurosis 6	2023-08-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg890*) 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). This variant is present in population databases (rs780587095, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of inherited retinal dystrophy (PMID: 11528500, 17525851). ClinVar contains an entry for this variant (Variation ID: 280091). For these reasons, this variant has been classified as Pathogenic.