X-38304746-C-T

Variant names:

• chrX-38304746-C-T
• rs62642057
• NM_001034853.2:c.823G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3_Supporting PP1_Moderate PP3_Strong PM2_Supporting PS4_Supporting PP4

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.823G>A (p.Gly275Ser) is a missense variant predicted to cause substitution of glycine by serine at amino acid 275. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 4 families, with 1 proband exhibiting a family history consistent with X-linked inheritance, functional vision impairment by age 30 years, decreased cone and rod electroretinogram responses, optic disc pallor, attenuation of vessels, pigmentary retinopathy, abnormal autofluorescence, reduced visual acuity, and abnormal color vision, which together are specific for RPGR-related retinopathy (4 points, PMID:17480003, PP4). This finding has been combined with reports of the variant in at least 2 additional apparently unrelated probands meeting the requirement of some functional vision impairment in affected males by age 30, with decreased or absent cone and/or rod electroretinogram responses (PMID:17480003, PMID:16969763, PS4_Supporting). The variant has been reported to segregate with the phenotype through 12 affected meioses in 2 families, meeting the ClinGen X-linked IRD VCEP PP1_Strong requirement of ≥4 meioses in >1 family (PP1_Strong; PMID:17480003). At least 4 other missense variants at the same codon (p.Gly275Arg, p.Gly275Cys, p.Gly275Val, and p.Gly275Asp) have been reported in association with retinal disease, however, all of them have a higher Grantham score than this variant, so PM5 is not met. The computational predictor REVEL gives a score of 0.968, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RPGR function (PP3_strong). Fluorescence microscopy-based localization assay performed with the p.Gly275Ser mutant and wild-type RPGR exogenously expressed as GFP-fusion proteins by RPE1 cells showed complete loss of localization to the primary cilia (PMID:30622176). Tag-based RPGR pull-down from HEK293T cells using anti-Flag beads followed by western blotting-based detection of endogenous PDE6D, RPGRIP1L, or INPP5 showed that the mutant had complete loss of interaction with INPP5E and RPGRIP1L, further indicating a damaging effect on protein function (PMID:30622176; PS3_Supporting). In summary, this variant meets the criteria to be 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; PS3_Supporting, PS4_Supporting, PM2_Supporting, PP1_Strong, PP3_Strong, and PP4. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226447/MONDO:0100437/106

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 5.74
• 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), 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 10 ACMG points.

• PS3: 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.
• PP3: 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.823G>A	p.Gly275Ser	missense	Exon 8 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.823G>A	p.Gly275Ser	missense	Exon 8 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.820G>A	p.Gly274Ser	missense	Exon 8 of 19	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.823G>A	p.Gly275Ser	missense	Exon 8 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-361375C>T		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000494841.1	TSL:1	n.86G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.78
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		5.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.94		Gain of catalytic residue at G275 (P = 0.0125)
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.0072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.95
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs62642057; hg19: chrX-38163999;