ClinVar Genomic variation as it relates to human health

This sequence change creates a premature translational stop signal (p.Glu809Glyfs*25) in the RPGR (ORF15) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 344 amino acid(s) of the RPGR (ORF15) protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 14566651, 20064120, 25775262). It has also been observed to segregate with disease in related individuals. This variant is also known as RPGR–ORF15 del673–674. ClinVar contains an entry for this variant (Variation ID: 183262). This variant disrupts a region of the RPGR (ORF15) protein in which other variant(s) (p.Leu1130Lysfs*13) have been determined to be pathogenic (PMID: 22264887; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

RPGR: PVS1:Strong, PM1, PM2, PS4:Moderate

The variant, c.2426_2427del (also known as c. 2425_2426del), results in the protein change, p.Glu809Glyfs*25. It has previously been reported in literature in several individuals affected by retinitis pigmentosa from different ethnicities: Czech, North American, Swedish, Japanese (Kousal et al., 2013; Liskova et al., 2011; Breuer et al., 2002; Vervoort et al., 2000; Andreasson et al., 2003; Jin at al., 2006) and familial segregation of this variant with retinitis pigmentosa phenotype has also been documented (Liskova et al., 2011; Jin et al., 2006). In one family, two affected cousins were identified to carry this variant, and despite similar age, the proband seemed to have a somewhat milder presentation without nyctalopia and with normal color vision and contrast sensitivity. The shared phenotypic features included bilateral myopia, astigmatism of varying severity, severely impaired contrast sensitivity and color vision, and bone spicules. None of the carriers exhibited typical bone spicules or a tapetal-like reflex (Kousal et al., 2013; Liskova et al., 2011). Breuer et al. (2002) identified this variant in two unrelated individuals with a diagnosis of retinitis pigmentosa. Jin et al. (2006) reported this variant in a father-daughter pair where the father reported a history of night blindness starting at age 10 and bone spicule-like changes in the midperipheral retina. The daughter reportedly had myopia and astigmatism at age 3 and tapetal-like reflex in bilateral fundi. This frameshift variant is located in the ORF15 region of RPGR that is translated in the clinically relevant transcript. Variants in the ORF15 region, which is a mutational hotspot where several other frameshift variants have been described, account for 30-63% of males with X-linked retinitis pigmentosa (Branham et al., 2012). The variant is absent in the 1000 genomes, NHLBI GO-ESP, and UK10K healthy datasets.

Converted during submission to Pathogenic.