X-38286761-TTCTC-TTC

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), PanelApp Australia
• RPGR-related retinopathy

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

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034853.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	NM_001034853.2	MANE Select	c.2236_2237delGA	p.Glu746ArgfsTer23	frameshift	Exon 15 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1905+331_1905+332delGA		intron	N/A	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1902+331_1902+332delGA		intron	N/A	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.2236_2237delGA	p.Glu746ArgfsTer23	frameshift	Exon 15 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-379356_172-379355delCT		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.2520+331_2520+332delGA		intron	N/A	ENSP00000343671.3	Q92834-1

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

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Retinitis pigmentosa 3 (6)
3	-	-	not provided (3)
3	-	-	Retinal dystrophy (3)
3	-	-	Retinitis pigmentosa (3)
1	-	-	Primary ciliary dyskinesia (1)
1	-	-	RPGR-related disorder (1)
1	-	-	RPGR-related retinopathy (1)
1	-	-	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 (1)

Computational scores

Source: dbNSFP v4.9

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;