X-38318909-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS3_Supporting PM2_Supporting PP4 PP3 PP1

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.389T>G (p.Phe130Cys) is a missense variant predicted to cause substitution of phenylalanine by cysteine 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 0.764, which is between the ClinGen X-linked IRD VCEP threshold of 0.644 to 0.773 and predicts a damaging effect on RPGR function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.05 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. The variant protein has shown severely decreased interaction with RPGRIP1 in a yeast-2-hybrid assay (PMID:10958648, PMID:23213406), as well as complete mislocalization to the cytoplasm rather than to the primary cilium (PMID:30622176) and disrupted interactions with PDE6D, RPGRIP1L, and INPP5E (PMID:30622176, PS3_supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1), family history consistent with X-linked inheritance (2) with a milder phenotype in females (1), pigmentary retinopathy (0.5), optic nerve pallor (0.5), and decreased central visual acuity (0.5), which together are specific for RPGR-related retinopathy (5.5 points, PP4, personal communication with clinician regarding an unpublished proband). The variant has been reported to segregate with retinal dystrophy through at least 1 affected meiosis (an affected mother and her son) from 1 family. (PP1, personal communication with author). 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; PS3_Supporting, PM2_Supporting, PP3, PP4, and PP1. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226418/MONDO:0100437/106

• Frequency: Genomes: not found (cov: 24)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:1 O:1
• 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 5 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.389T>G	p.Phe130Cys	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>G	p.Phe130Cys	missense_variant	Exon 5 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-347212A>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Other:1

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinitis pigmentosa 3 Pathogenic:1

Sep 15, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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>G (p.Phe130Cys) is a missense variant predicted to cause substitution of phenylalanine by cysteine 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 0.764, which is between the ClinGen X-linked IRD VCEP threshold of 0.644 to 0.773 and predicts a damaging effect on RPGR function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.05 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. The variant protein has shown severely decreased interaction with RPGRIP1 in a yeast-2-hybrid assay (PMID: 10958648, PMID: 23213406), as well as complete mislocalization to the cytoplasm rather than to the primary cilium (PMID: 30622176) and disrupted interactions with PDE6D, RPGRIP1L, and INPP5E (PMID: 30622176, PS3_supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1), family history consistent with X-linked inheritance (2) with a milder phenotype in females (1), pigmentary retinopathy (0.5), optic nerve pallor (0.5), and decreased central visual acuity (0.5), which together are specific for RPGR-related retinopathy (5.5 points, PP4, personal communication with clinician regarding an unpublished proband). The variant has been reported to segregate with retinal dystrophy through at least 1 affected meiosis (an affected mother and her son) from 1 family. (PP1, personal communication with author). 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; PS3_Supporting, PM2_Supporting, PP3, PP4, and PP1. (date of approval 05/16/2025). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.61	.;.;D;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;.;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.2	M;M;M;.;M;M;M;.;.
PhyloP100		8.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.1	D;.;D;.;.;.;D;.;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.014	D;.;D;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;.;D;.;.;.;D;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.
Vest4		0.93
MutPred		0.60		Loss of stability (P = 0.018);Loss of stability (P = 0.018);Loss of stability (P = 0.018);Loss of stability (P = 0.018);Loss of stability (P = 0.018);Loss of stability (P = 0.018);Loss of stability (P = 0.018);.;Loss of stability (P = 0.018);
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.87
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;