rs62638634

Variant names:

• chrX-38322921-C-A
• rs62638634
• NM_001034853.2:c.179G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP1_Moderate PS3_Supporting PP3_Strong PM2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.179G>T (p.Gly60Val) is a missense variant that replaces glycine with valine at amino acid 60. 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), visual field reduction (0.5 pts), central vision problem (0.5 pts) since 6 years of age (1 pt), poor night vision (0.5 pts), pigmentary retinopathy (0.5 pts), and nondetectable electroretinogram responses, which together are specific for RPGR-related retinopathy (6 points, PMID:9855162, PP4). This variant has been reported in other publications, however, the ability to conclude that the probands described are unrelated was not successful (PMIDs: 28559085, 10937588, 34985506, 9399904, 9855162). The variant has been reported to segregate with retinal dystrophy through at least 4 meioses from at least 1 family (PP1_moderate; PMID: [9855162]). The computational predictor REVEL gives a score of 0.98, 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 0.19 for acceptor loss, 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 in a yeast-2-hybrid experiment (PMID:23213406, 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, PP1_moderate, PP3_strong, PS3_supporting, and PP4. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226376/MONDO:0100437/106

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 O:1
• Conservation: PhyloP100: 7.52
• Publications: 4 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: 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.
• PP3: 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.179G>T	p.Gly60Val	missense_variant	Exon 3 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.179G>T	p.Gly60Val	missense_variant	Exon 3 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-343200C>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Other:1

Sep 16, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RPGR c.179G>T; p.Gly60Val variant (rs62638634) has been reported in several individuals with X-linked retinitis pigmentosa (Buraczynska 1997, Sharon 2000, Stone 2017) and has been reported to segregate with disease in at least one family (Fishman 1998). The variant is reported in the ClinVar database (Variation ID: 9902) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 60 is highly conserved, computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious, and structural analysis predicts this amino acid is critical in protein function and the variant causes reduced protein interaction (Patil 2012). Considering available information, this variant is classified as pathogenic. References: Buraczynska M et al. Spectrum of mutations in the RPGR gene that are identified in 20% of families with X-linked retinitis pigmentosa. Am J Hum Genet. 1997 Dec;61(6):1287-92. Fishman GA et al. X-linked retinitis pigmentosa in two families with a missense mutation in the RPGR gene and putative change of glycine to valine at codon 60. Ophthalmology. 1998 Dec;105(12):2286-96. Patil H et al. Structural and functional plasticity of subcellular tethering, targeting and processing of RPGRIP1 by RPGR isoforms. Biol Open. 2012 Feb 15;1(2):140-60. Sharon D et al. X-linked retinitis pigmentosa: mutation spectrum of the RPGR and RP2 genes and correlation with visual function. Invest Ophthalmol Vis Sci. 2000 Aug;41(9):2712-21. Stone EM et al. Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology. 2017 Sep;124(9):1314-1331. -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 10, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23536988, 10937588, 28559085, 10958647, 19815619, 20631154, 23213406, 38586605, 34985506, 9399904, 9855162) -

RPGR-related disorder Pathogenic:1

Jun 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RPGR c.179G>T variant is predicted to result in the amino acid substitution p.Gly60Val. This variant has been reported in individuals with retinitis pigmentosa (Buraczynska et al. 1997. PubMedID: 9399904; Sharon et al. 2003. PubMed ID: 14564670; Table S3, Tuupanen et al. 2022. PubMed ID: 34985506). An in silico functional study suggests this variant causes misfolding of a particular domain of the protein (Patil et al. 2012. PubMed ID: 23213406). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/9902/). Given the evidence, we interpret this variant as pathogenic. -

Retinitis pigmentosa 3 Pathogenic:1

Dec 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Primary ciliary dyskinesia Pathogenic:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 60 of the RPGR protein (p.Gly60Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 9399904, 9855162, 10937588). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9902). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RPGR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect RPGR function (PMID: 19815619, 20631154). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:1

May 19, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RPGR-related retinopathy Pathogenic:1

May 20, 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.179G>T (p.Gly60Val) is a missense variant that replaces glycine with valine at amino acid 60. 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), visual field reduction (0.5 pts), central vision problem (0.5 pts) since 6 years of age (1 pt), poor night vision (0.5 pts), pigmentary retinopathy (0.5 pts), and nondetectable electroretinogram responses, which together are specific for RPGR-related retinopathy (6 points, PMID: 9855162, PP4). This variant has been reported in other publications, however, the ability to conclude that the probands described are unrelated was not successful (PMIDs: 28559085, 10937588, 34985506, 9399904, 9855162). The variant has been reported to segregate with retinal dystrophy through at least 4 meioses from at least 1 family (PP1_moderate; PMID: [9855162]). The computational predictor REVEL gives a score of 0.98, 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 0.19 for acceptor loss, 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 in a yeast-2-hybrid experiment (PMID: 23213406, 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, PP1_moderate, PP3_strong, PS3_supporting, and PP4. (date of approval 05/16/2025). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;.;D;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;.;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.5	H;H;H;.;H;H;H;.
PhyloP100		7.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-8.0	D;.;D;.;.;.;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;D;.;.;.;D;.
Polyphen		1.0	D;D;.;.;.;.;.;.
Vest4		0.93
MutPred		0.90		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		5.9
Varity_R		1.0
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs62638634; hg19: chrX-38182174;