Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001034853.2(RPGR):c.283G>A (p.Gly95Arg)

CA412745404

2430151 (ClinVar)

Gene: RPGR (HGNC:6103)
Condition: RPGR-related retinopathy (MONDO:0100437)
Inheritance Mode: X-linked inheritance
UUID: d875bbdf-5dd9-426a-b1f6-191b95cdb435
Approved on: 2025-09-05
Published on: 2025-09-05

HGVS expressions

NM_001034853.2(RPGR):c.283G>A (p.Gly95Arg)
NM_001034853.2:c.283G>A
NC_000023.11:g.38321054C>T
CM000685.2:g.38321054C>T
NC_000023.10:g.38180307C>T
CM000685.1:g.38180307C>T
NC_000023.9:g.38065251C>T
NG_009553.1:g.11482G>A
ENST00000642170.1:n.693G>A
ENST00000642373.1:c.283G>A
ENST00000642395.2:c.283G>A
ENST00000642558.1:c.190G>A
ENST00000642739.1:c.283G>A
ENST00000644238.1:c.283G>A
ENST00000644337.1:c.283G>A
ENST00000645032.1:c.283G>A
ENST00000645124.1:c.283G>A
ENST00000646020.1:c.283G>A
ENST00000647261.1:c.283G>A
ENST00000318842.11:c.283G>A
ENST00000339363.7:c.283G>A
ENST00000378505.6:c.283G>A
ENST00000465127.1:c.172-345067C>T
ENST00000474584.5:c.283G>A
ENST00000482855.5:c.283G>A
NM_000328.2:c.283G>A
NM_001034853.1:c.283G>A
NM_001367245.1:c.283G>A
NM_001367246.1:c.283G>A
NM_001367247.1:c.283G>A
NM_001367248.1:c.313G>A
NM_001367249.1:c.283G>A
NM_001367250.1:c.283G>A
NM_001367251.1:c.283G>A
NR_159803.1:n.425G>A
NR_159804.1:n.425G>A
NR_159805.1:n.425G>A
NR_159806.1:n.425G>A
NR_159807.1:n.425G>A
NR_159808.1:n.693G>A
NM_000328.3:c.283G>A
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Pathogenic

Met criteria codes 5
PP3_Strong PP4_Moderate PM2_Supporting PP1_Moderate PM5_Supporting
Not Met criteria codes 3
PS4 BA1 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
X-linked Inherited Retinal Disease VCEP
NM_001034853.2(RPGR):c.283G>A (p.Gly95Arg) is a missense variant that replaces glycine with arginine at amino acid 95. Another missense variant in the same codon, NM_001034853.2(RPGR):c.284G>A (p.Gly95Glu) (PMID: 33598457), has 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 (125) than the comparison variant (98), and SpliceAI has been used to confirm that neither variant has a predicted impact on RPGR splicing (PM5_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits rod-cone dystrophy (1 pt) with onset during the teens (1 pt), genotyping by next-generation sequencing with a 105-gene panel that did not identify an alternative cause of retinal disease (2 pts), family history consistent with X-linked inheritance (2 pt) with female family members showing milder phenotypes (1 pt), reduced visual acuity (0.5 pts), and fundus mid-peripheral atrophy (0.5 pts), which together are highly specific for RPGR-related retinopathy (8 total pts, PMID: 28488341; PMID: 36882936, PP4_Moderate). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_Moderate; PMID: 28488341, PMID: 36882936). The computational predictor REVEL gives a score of 0.972, 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 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. In summary, this variant is 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; PM2_Supporting, PM5_Supporting, PP1_Moderate, PP3_Strong, and PP4_Moderate.
Met criteria codes
PP3_Strong
The computational predictor REVEL gives a score of 0.972, 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 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.
PP4_Moderate
At least one proband harboring this variant exhibits rod-cone dystrophy (1 pt) with onset during the teens (1 pt), genotyping by next-generation sequencing with a 105-gene panel that did not identify an alternative cause of retinal disease (2 pts), family history consistent with X-linked inheritance (2 pt) with female family members showing milder phenotypes (1 pt), reduced visual acuity (0.5 pts), and fundus mid-peripheral atrophy and pigment (0.5 pts) (8 total pts, PMID: 28488341; PMID: 36882936, PP4_Moderate).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
PP1_Moderate
The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_moderate; PMID: 28488341, PMID: 36882936).
PM5_Supporting
Another missense variant in the same codon, NM_001034853.2(RPGR):c.284G>A (p.Gly95Glu) (PMID: 33598457), has 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 (125) than the comparison variant (98), and SpliceAI has been used to confirm that neither variant has a predicted impact on RPGR splicing (PM5_Supporting).
Not Met criteria codes
PS4
This variant has been reported in at least 1 proband not meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 and/or decreased or absent ERG responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 28863407).
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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