rs730882261

chrX-38286571-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001034853.2(RPGR):c.2426_2427del(p.Glu809GlyfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E809E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 7)
• Consequence: RPGR NM_001034853.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: -0.0420

Genes affected

RPGR (HGNC:10295): (retinitis pigmentosa GTPase regulator) This gene encodes a protein with a series of six RCC1-like domains (RLDs), characteristic of the highly conserved guanine nucleotide exchange factors. The encoded protein is found in the Golgi body and interacts with RPGRIP1. This protein localizes to the outer segment of rod photoreceptors and is essential for their viability. Mutations in this gene have been associated with X-linked retinitis pigmentosa (XLRP). Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length natures of only some have been determined. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 98 pathogenic variants in the truncated region.
• PP5: Variant X-38286571-CCT-C is Pathogenic according to our data. Variant chrX-38286571-CCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38286571-CCT-C is described in Lovd as [Likely_pathogenic]. Variant chrX-38286571-CCT-C is described in Lovd as [Pathogenic]. Variant chrX-38286571-CCT-C is described in Lovd as [Pathogenic]. Variant chrX-38286571-CCT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.2426_2427del	p.Glu809GlyfsTer25	frameshift_variant	15/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.2426_2427del	p.Glu809GlyfsTer25	frameshift_variant	15/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes Cov.: 7

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 7

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 3 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2000	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	RPGR: PVS1:Strong, PM1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 06, 2016	- -

Retinal dystrophy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 09, 2019	- -

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

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. -

Retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

research

Personalis, Inc.

Aug 25, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730882261; hg19: chrX-38145824;