rs137852550

Variant names:

• chrX-38317418-C-G
• rs137852550
• NM_001034853.2:c.517G>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001034853.2(RPGR):​c.517G>C​(p.Gly173Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 5.81
• Publications: 6 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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001034853.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-38317418-C-G is Pathogenic according to our data. Variant chrX-38317418-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 9916.Status of the report is reviewed_by_expert_panel, 3 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	NM_001034853.2	MANE Select	c.517G>C	p.Gly173Arg	missense	Exon 6 of 15	NP_001030025.1
	RPGR	NM_000328.3		c.517G>C	p.Gly173Arg	missense	Exon 6 of 19	NP_000319.1
	RPGR	NM_001367245.1		c.517G>C	p.Gly173Arg	missense	Exon 6 of 19	NP_001354174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.517G>C	p.Gly173Arg	missense	Exon 6 of 15	ENSP00000495537.1
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-348703C>G		intron	N/A	ENSP00000417050.1
	RPGR	ENST00000339363.7	TSL:5	c.517G>C	p.Gly173Arg	missense	Exon 6 of 18	ENSP00000343671.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

RETINITIS PIGMENTOSA, SINORESPIRATORY INFECTIONS, AND DEAFNESS Pathogenic:1

Nov 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Aug 25, 2016

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RPGR-related retinopathy Pathogenic:1

Sep 07, 2025

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_001034853.2(RPGR):c.517G>C (p.Gly173Arg) is a missense variant encoding the substitution of glycine by arginine at amino acid 173. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts) showing a milder phenotype in female family members (1 pt), early-onset (1 pt), rod involvement greater than cone (1 pt), visual field constriction (0.5 pts), night blindness (0.5 pts), myopia (0.5 pts), and reduced visual acuity (0.5 pts), which together are specific for RPGR-related retinopathy (7 points, PMID: 14627685, PP4). The proband also showed systemic phenotypes including episodes of respiratory tract infections, recurrent ear infections, pan-sinusitis, and a mild high frequency hearing loss (PMID: 14627685). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_Moderate; PMID: 14627685). The computational predictor REVEL gives a score of 0.972, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RPGR function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.09 for donor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. Exogenously expressed RPGR harboring the variant exhibits reduced interaction with RPGRIP1 and RAB8A in yeast-2-hybrid and pulldown experiments (PMID: 20631154, PMID: 23213406, PS3_Supporting). In summary, this variant is classified as likely 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; PM2_supporting, PP3_Strong, PS3_Supporting, PP1_Moderate, and PP4.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.78
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		5.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.94		Loss of ubiquitination at K175 (P = 0.0508)
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs137852550; hg19: chrX-38176671;