NM_001034853.2:c.2236_2237delGA

Variant names:

• chrX-38286761-TTC-T
• rs1555961852
• NM_001034853.2:c.2236_2237delGA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PP1_Strong PS4 PVS1 PM2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.2236_2237del (p.Glu746ArgfsTer23) is a frameshift variant that introduces a premature stop codon into exon 15 of 15 before amino acid 1132, which is predicted not to trigger nonsense-mediated decay but rather to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID:36445968). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_supporting). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts), with delayed or milder phenotype in females (1 pt), and rod involvement greater than cone (1 pt), which together are specific for RPGR-related retinopathy (4 points, PP4). This variant has been reported in at least 33 apparently unrelated probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years, or decreased / absent cone and/or rod electroretinogram responses (PMIDs: 20021257, 11950860, 16086276, 17093403, 34745198, 33247286, 33576794, 33090715, 23681342, 31213501, 22807293, 32531858, PS4). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from at least 2 families (PP1_strong; PMID:21857984, 20021257, 11950860, 16086276, 17093403, 34745198). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4, PM2_supporting, PP1_strong, and PP4. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA645509417/MONDO:0100437/106

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 0.0000048 (0 hom. 0 hem.)
• Consequence: RPGR NM_001034853.2 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:19
• Conservation: PhyloP100: 0.522
• Publications: 5 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 18 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.2236_2237delGA	p.Glu746ArgfsTer23	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.2236_2237delGA	p.Glu746ArgfsTer23	frameshift_variant	Exon 15 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-379356_172-379355delCT		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome AF: 0.00000475 AC: 5 AN: 1052096 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 343200

African (AFR) AF: 0.00 AC: 0 AN: 24896

American (AMR) AF: 0.00 AC: 0 AN: 27884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18491

East Asian (EAS) AF: 0.00 AC: 0 AN: 27155

South Asian (SAS) AF: 0.00 AC: 0 AN: 49494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3451

European-Non Finnish (NFE) AF: 0.00000488 AC: 4 AN: 818910

Other (OTH) AF: 0.0000225 AC: 1 AN: 44357

GnomAD4 genome Cov.: 16

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

Submissions by phenotype

Retinitis pigmentosa 3 Pathogenic:6

-

Blueprint Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 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: VCV000438142 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 01, 2016

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 21, 2020

Institute of Medical Molecular Genetics, University of Zurich

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 26, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP5. This variant was detected in hemizygous state. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Strong+PM2_Supporting+PS4+PM6_Supporting+PP4 -

not provided Pathogenic:3

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RPGR: PVS1:Strong, PM2, PS4:Moderate, PP1, PP4 -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 407 amino acids are lost and replaced with 22 incorrect amino acids (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28512305, 29190250, 27798110, 28041643, 16086276, 10932196, 29099798, 20021257, 28863407, 23150612, 32141364, 33090715, 31953110, 31106028, 33576794, 33781268, 35432464, 34985506) -

Retinal dystrophy Pathogenic:3

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 07, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:3

Apr 01, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Glu746ArgfsTer23 variant in RPGR was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 09, 2020

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

X-linked cone-rod dystrophy 1;C1845667:Retinitis pigmentosa 3;C2749137:Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness;C3151784:Macular degeneration, X-linked atrophic Pathogenic:1

Mar 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RPGR-related disorder Pathogenic:1

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RPGR c.2236_2237delGA variant is predicted to result in a frameshift and premature protein termination (p.Glu746Argfs*23). This variant can also be denoted as g.ORF15+483_484del. This variant has been reported several times in patients with X-linked retinitis pigmentosa (Vervoort et al. 2000. PubMed ID: 10932196; Branham et al. 2012. PubMed ID: 23150612; Table S2, Carss et al. 2016. PubMed ID: 28041643; Maggi et al. 2020. PubMed ID: 32679846). This variant has not been reported in the large population database gnomAD, indicating this variant is rare. This variant has been interpreted as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/438142), and frameshift variants in RPGR are an established mechanism of disease. Given all the evidence, we interpret this variant as pathogenic. -

Primary ciliary dyskinesia Pathogenic:1

Dec 19, 2024

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.Glu746Argfs*23) in the RPGR (ORF15) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 407 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: 10932196, 20021257). This variant is also known as g.ORF15+483_484delGA. ClinVar contains an entry for this variant (Variation ID: 438142). 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. -

RPGR-related retinopathy Pathogenic:1

May 20, 2025

ClinGen X-linked Inherited Retinal Disease Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_001034853.2(RPGR):c.2236_2237del (p.Glu746ArgfsTer23) is a frameshift variant that introduces a premature stop codon into exon 15 of 15 before amino acid 1132, which is predicted not to trigger nonsense-mediated decay but rather to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_supporting). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts), with delayed or milder phenotype in females (1 pt), and rod involvement greater than cone (1 pt), which together are specific for RPGR-related retinopathy (4 points, PP4). This variant has been reported in at least 33 apparently unrelated probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years, or decreased / absent cone and/or rod electroretinogram responses (PMIDs: 20021257, 11950860, 16086276, 17093403, 34745198, 33247286, 33576794, 33090715, 23681342, 31213501, 22807293, 32531858, PS4). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from at least 2 families (PP1_strong; PMID: 21857984, 20021257, 11950860, 16086276, 17093403, 34745198). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4, PM2_supporting, PP1_strong, and PP4. (date of approval 05/16/2025). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.52
Mutation Taster		=1/199	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: rs1555961852; hg19: chrX-38146014;