rs730882261

Variant names:

• chrX-38286571-CCT-C
• rs730882261
• NM_001034853.2:c.2426_2427delAG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001034853.2(RPGR):​c.2426_2427delAG​(p.Glu809GlyfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E809E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 7)
• Consequence: RPGR NM_001034853.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: -0.0420
• Publications: 9 publications found

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]

RPGR Gene-Disease associations (from GenCC):

• retinitis pigmentosa 3

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• RPGR-related retinopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• primary ciliary dyskinesia-retinitis pigmentosa syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• macular degeneration, X-linked atrophic

  Inheritance: XL Classification: LIMITED Submitted by: G2P

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 278 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 Pathogenic. ClinVar VariationId is 183262.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.2426_2427delAG	p.Glu809GlyfsTer25	frameshift_variant	Exon 15 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.2426_2427delAG	p.Glu809GlyfsTer25	frameshift_variant	Exon 15 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-379547_172-379546delCT		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 3 Pathogenic:4

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Blueprint Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 23, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000183262). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:3

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 06, 2016

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in multiple unrelated patients with X-linked retinitis pigmentosa in published literature (PMID: 10932196); Frameshift 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: 32141364, 31953110, 32000842, 33546218, 23822596, 20064120, 17093403, 14566651, 11992260, 34659350, 34985506, 30567410, 18552978, 32094925, 32860923, 25775262, 30543658, 37510321, 38117582, 36276946, 36050475, 38586605, 37284979, 33090715, 10932196) -

Retinal dystrophy Pathogenic:3

Aug 09, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 01, 2015

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Pathogenic:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). 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

Aug 25, 2014

Personalis, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.042
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs730882261; hg19: chrX-38145824;