X-38318909-A-G

Variant names:

• chrX-38318909-A-G
• rs62638644
• NM_001034853.2:c.389T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2_Supporting PP3

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.389T>C (p.Phe130Ser) is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 130. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives the variant a score of 0.761, which is between the ClinGen X-linked IRD VCEP thresholds of 0.664 to 0.772 and predicts a damaging effect on RPGR function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.01 for donor loss, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. At least 1 patient with this variant has been diagnosed with X-linked retinopathy, but phenotype details necessary to meet PP4 or include the patient in PS4_Supporting have not been reported (PMID:28863407, PMID:32531858, SCV001162677.1). Another missense variant in the same codon, NM_001034853.2(RPGR):c.389T>G (p.Phe130Cys), has been reported in a patient with X-linked retinopathy (PMID:8817343). However, the present variant has a lower Grantham score (155) than the comparison variant (205), so that the PM5 code cannot be evaluated. In summary, this variant is classified as a variant of uncertain significance 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 and PP3. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA412745161/MONDO:0100437/106

• Frequency: Genomes: not found (cov: 24)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 8.79
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.389T>C	p.Phe130Ser	missense_variant	Exon 5 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.389T>C	p.Phe130Ser	missense_variant	Exon 5 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-347212A>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Retinitis pigmentosa Pathogenic:1

Jan 09, 2020

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Primary ciliary dyskinesia Uncertain:1

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the RPGR protein (p.Phe130Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 32531858). ClinVar contains an entry for this variant (Variation ID: 813227). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RPGR protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

RPGR-related retinopathy Uncertain:1

May 20, 2025

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

NM_001034853.2(RPGR):c.389T>C (p.Phe130Ser) is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 130. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives the variant a score of 0.761, which is between the ClinGen X-linked IRD VCEP thresholds of 0.664 to 0.772 and predicts a damaging effect on RPGR function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.01 for donor loss, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. At least 1 patient with this variant has been diagnosed with X-linked retinopathy, but phenotype details necessary to meet PP4 or include the patient in PS4_Supporting have not been reported (PMID: 28863407, PMID: 32531858, SCV001162677.1). Another missense variant in the same codon, NM_001034853.2(RPGR):c.389T>G (p.Phe130Cys), has been reported in a patient with X-linked retinopathy (PMID: 8817343). However, the present variant has a lower Grantham score (155) than the comparison variant (205), so that the PM5 code cannot be evaluated. In summary, this variant is classified as a variant of uncertain significance 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 and PP3. (date of approval 05/16/2025). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;.;T;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;.;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.2	M;M;M;.;M;M;M;.;.
PhyloP100		8.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.1	D;.;D;.;.;.;D;.;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.015	D;.;T;.;.;.;.;.;.
Sift4G	Uncertain	0.0040	D;.;D;.;.;.;D;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.
Vest4		0.87
MutPred		0.64		Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);.;Loss of stability (P = 0.0037);
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.93
gMVP		0.99
Mutation Taster		=0/100	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: rs62638644; hg19: chrX-38178162;