rs398122960

Variant names:

• chrX-38286592-CCT-C
• rs398122960
• NM_001034853.2:c.2405_2406delAG

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PP1_Strong PS4 PP4_Moderate PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.2405_2406del (p.Glu802GlyfsTer?) 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). This variant has been reported in at least 6 apparently unrelated probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years and/or decreased or absent cone and/or rod electroretinogram responses (PMID:34745198, 29453956, 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:34745198, 21857984). 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, and PP1_strong. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA266215/MONDO:0100437/106

• Frequency:
  • Genomes: not found (cov: 8)
  • Exomes 𝑓: 0.0000038 (0 hom. 1 hem.)
• Consequence: RPGR NM_001034853.2 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:20
• Conservation: PhyloP100: 0.498
• Publications: 29 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 19 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.2405_2406delAG	p.Glu802GlyfsTer32	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.2405_2406delAG	p.Glu802GlyfsTer32	frameshift_variant	Exon 15 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-379526_172-379525delCT		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 8

GnomAD4 exome AF: 0.00000384 AC: 4 AN: 1041524 Hom.: 0 AF XY: 0.00000298 AC XY: 1 AN XY: 335196

African (AFR) AF: 0.00 AC: 0 AN: 24583

American (AMR) AF: 0.00 AC: 0 AN: 27357

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18077

East Asian (EAS) AF: 0.0000373 AC: 1 AN: 26816

South Asian (SAS) AF: 0.00 AC: 0 AN: 48432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2817

European-Non Finnish (NFE) AF: 0.00000369 AC: 3 AN: 812462

Other (OTH) AF: 0.00 AC: 0 AN: 43798

GnomAD4 genome Cov.: 8

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Jul 14, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Also known as g.ORF15+652_653delAG using alternate nomenclature; Frameshift variant predicted to result in protein truncation, as the last 351 amino acids are replaced with 31 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25494902, 24938718, 24043777, 29190250, 30567410, 20021257, 27032803, 10932196, 22264887, 28322733, 18552978, 29785639, 31953110, 33355362, 31054281, 32000842, 32702353, 31047384, 30543658, 33090715, 33576794, 33946315, 24077912) -

Aug 29, 2016

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 3 Pathogenic:3

Aug 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 11, 2017

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2023

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: VCV000091389). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Retinal dystrophy Pathogenic:3

Aug 25, 2017

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, 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

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 24, 2023

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Clinical significance based on ACMG v2.0 -

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.Glu802GlyfsTer32 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. -

X-linked cone-rod dystrophy 1 Pathogenic:2

Feb 09, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PP5 -

Aug 02, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Oct 12, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Pathogenic:1

Jan 20, 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.Glu802Glyfs*32) in the RPGR (ORF15) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 351 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 individuals with retinitis pigmentosa (PMID: 10932196, 18552978, 20021257, 22264887, 25544989). It has also been observed to segregate with disease in related individuals. This variant is also known as g.ORF15+652_653delAG. ClinVar contains an entry for this variant (Variation ID: 91389). 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.2405_2406del (p.Glu802GlyfsTer?) 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). This variant has been reported in at least 6 apparently unrelated probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years and/or decreased or absent cone and/or rod electroretinogram responses (PMID: 34745198, 29453956, 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: 34745198, 21857984). 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, and PP1_strong. (date of approval 05/16/2025). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.50
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: rs398122960; hg19: chrX-38145845;