rs62638637

Variant names:

• chrX-38321041-G-A
• rs62638637
• NM_001034853.2:c.296C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-38321041-G-A
• chrX-38321041-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3_Moderate PP1_Moderate PM5_Supporting PM2_Supporting PS4_Supporting PP4

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.296C>T (p.Thr99Ile) is a missense variant predicted to substitute threonine with isoleucine at amino acid 99. 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 early onset (1 pt), a family history consistent with X-linked inheritance (2 pt), visual field constriction (0.5 pts), and rod involvement greater than cone (1 pt), which together are specific for RPGR-related retinopathy (4.5pts, PMID:21857984, PP4). This variant has been reported in at least 2 additional apparently unrelated probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years or decreased or absent cone and/or rod electroretinogram responses (PMID:32702353, 31213501, 21857984, PS4_supporting). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_moderate; PMID:21857984). Another missense variant in the same codon, NM_001034853.2(RPGR):c.296C>A (p.Thr99Asn), (PMIDs: 32531858, 32702353, 10482958, and 28863407) has previously been classified as likely pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (89) than the comparison variant (65), and SpliceAI has been used to confirm that neither variant has a predicted impact on RPGR splicing (PM5_Supporting). The computational predictor REVEL gives a score of 0.813, which is between the ClinGen X-linked IRD VCEP threshold of 0.773 to 0.931 and predicts a damaging effect on RPGR function (PP3_moderate). The computational splicing predictor SpliceAI gives a delta score of 0.03 for acceptor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. 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, PM5_supporting, PP1_moderate, PP3_moderate, and PP4. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA412745374/MONDO:0100437/106

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 9.55
• Publications: 0 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 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.296C>T	p.Thr99Ile	missense_variant	Exon 4 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.296C>T	p.Thr99Ile	missense_variant	Exon 4 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-345080G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

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.296C>T (p.Thr99Ile) is a missense variant predicted to substitute threonine with isoleucine at amino acid 99. 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 early onset (1 pt), a family history consistent with X-linked inheritance (2 pt), visual field constriction (0.5 pts), and rod involvement greater than cone (1 pt), which together are specific for RPGR-related retinopathy (4.5pts, PMID: 21857984, PP4). This variant has been reported in at least 2 additional apparently unrelated probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years or decreased or absent cone and/or rod electroretinogram responses (PMID: 32702353, 31213501, 21857984, PS4_supporting). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_moderate; PMID: 21857984). Another missense variant in the same codon, NM_001034853.2(RPGR):c.296C>A (p.Thr99Asn), (PMIDs: 32531858, 32702353, 10482958, and 28863407) has previously been classified as likely pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (89) than the comparison variant (65), and SpliceAI has been used to confirm that neither variant has a predicted impact on RPGR splicing (PM5_Supporting). The computational predictor REVEL gives a score of 0.813, which is between the ClinGen X-linked IRD VCEP threshold of 0.773 to 0.931 and predicts a damaging effect on RPGR function (PP3_moderate). The computational splicing predictor SpliceAI gives a delta score of 0.03 for acceptor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. 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, PM5_supporting, PP1_moderate, PP3_moderate, and PP4. (date of approval 05/16/2025). -

Retinal dystrophy Uncertain:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;.;D;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	.;T;T;T;T;.;T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.3	M;M;M;.;M;M;M;.;.
PhyloP100		9.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.8	D;.;D;.;.;.;D;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.018	D;.;D;.;.;.;.;.;.
Sift4G	Uncertain	0.050	T;.;T;.;.;.;D;.;.
Polyphen		0.98	D;D;.;.;.;.;.;.;.
Vest4		0.81
MutPred		0.65		Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);.;Loss of disorder (P = 0.0377);
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.92
gMVP		0.99
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.030		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: rs62638637; hg19: chrX-38180294;