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.178G>A (p.Gly60Ser)

CA412745655

1676154 (ClinVar)

Gene: RPGR (HGNC:6103)
Condition: RPGR-related retinopathy (MONDO:0100437)
Inheritance Mode: X-linked inheritance (dominant (HP:0001423))
UUID: 2e328e2b-d75b-41e5-83fd-345b83e7b508
Approved on: 2025-08-03
Published on: 2025-08-04

HGVS expressions

NM_001034853.2:c.178G>A
NM_001034853.2(RPGR):c.178G>A (p.Gly60Ser)
NC_000023.11:g.38322922C>T
CM000685.2:g.38322922C>T
NC_000023.10:g.38182175C>T
CM000685.1:g.38182175C>T
NC_000023.9:g.38067119C>T
NG_009553.1:g.9614G>A
ENST00000642170.1:n.588G>A
ENST00000642373.1:c.178G>A
ENST00000642395.2:c.178G>A
ENST00000642558.1:c.154+477G>A
ENST00000642739.1:c.178G>A
ENST00000644238.1:c.178G>A
ENST00000644337.1:c.178G>A
ENST00000645032.1:c.178G>A
ENST00000645124.1:c.178G>A
ENST00000646020.1:c.178G>A
ENST00000647261.1:c.178G>A
ENST00000318842.11:c.178G>A
ENST00000339363.7:c.178G>A
ENST00000378505.6:c.178G>A
ENST00000465127.1:c.172-343199C>T
ENST00000474584.5:c.178G>A
ENST00000482855.5:c.178G>A
NM_000328.2:c.178G>A
NM_001034853.1:c.178G>A
NM_001367245.1:c.178G>A
NM_001367246.1:c.178G>A
NM_001367247.1:c.178G>A
NM_001367248.1:c.208G>A
NM_001367249.1:c.178G>A
NM_001367250.1:c.178G>A
NM_001367251.1:c.178G>A
NR_159803.1:n.320G>A
NR_159804.1:n.320G>A
NR_159805.1:n.320G>A
NR_159806.1:n.320G>A
NR_159807.1:n.320G>A
NR_159808.1:n.588G>A
NM_000328.3:c.178G>A
More

Likely Pathogenic

Met criteria codes 4
PP3_Strong PP1 PP4 PM2_Supporting
Not Met criteria codes 12
PS4 PS3 PP2 PM1 PM5 BA1 BS2 BS4 BS3 BS1 BP4 BP1

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.178G>A (p.Gly60Ser) is a predicted missense variant that replaces glycine with serine at amino acid 60. Another missense variant in the same codon, NM_001034853.2(RPGR):c.179G>T (p.Gly60Val), has been classified as pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. However, the present variant has a lower Grantham’s distance (56) than the comparison variant (109), so the PM5_Supporting code is not met. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of rod-cone dystrophy with childhood onset (1 pt), electroretinogram confirmation of rod involvement greater than cone (1pt), genotyping by next-generation sequencing using a 105-gene panel that did not identify an alternative cause of retinal disease (2 pts), family history consistent with X-linked inheritance (2 pts), night blindness (0.5 pts), and photophobia (0.5 pts), which together are specific for RPGR-related retinopathy (7 points, PMID: 28341476, https://c.peervoice.com/programs/505204504/downloads/PV_transcript_CHS_EN.pdf, PP4). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family (PP1; PMID: 28341476). The computational predictor REVEL gives a score of 0.944, which is above the ClinGen X-linked IRD VCEP threshold of ≥ 0.932 and predicts a damaging effect on RPGR function (PP3_Strong). Also, the computational splicing predictor SpliceAI gives delta scores of 0.35 for acceptor loss and 0.33 for donor loss, which are above the ClinGen X-linked IRD VCEP threshold of >0.2 and predict a damaging impact on 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, PP4, PP1, and PP3_Strong. (date of approval 05/16/2025).
Met criteria codes
PP3_Strong
The computational predictor REVEL gives a score of 0.944, which is above the ClinGen X-linked IRD VCEP threshold of ≥ 0.932 and predicts a damaging effect on RPGR function (PP3_strong). In addition, the computational splicing predictor SpliceAI gives a delta score of 0.35 for acceptor loss, which is above the ClinGen X-linked IRD VCEP threshold of >0.2 and predicts a damaging impact on splicing.
PP1
The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family (PP1; PMID: 28341476, https://c.peervoice.com/programs/505204504/downloads/PV_transcript_CHS_EN.pdf).
PP4
At least one proband harboring this variant exhibits a phenotype including diagnosis of childhood-onset (1 pt) rod-cone dystrophy (rod involvement greater than cone, 1pt) with next-generation sequencing-based genotyping using a 105-gene panel that did not find an alternative cause of retinal disease (2 pts), family history consistent with X-linked inheritance (2 pts), night blindness (0.5 pts), and photophobia (0.5 pts), which together are specific for RPGR-related retinopathy (7 points, PMID: 28341476, https://c.peervoice.com/programs/505204504/downloads/PV_transcript_CHS_EN.pdf, PP4).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
Not Met criteria codes
PS4
This variant has been reported in at least 1 proband meeting the PS4 requirement of some functional vision impairment in affected males by age 30 (PMID: 28341476). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met.
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
The ClinGen X-linked IRD VCEP has previously classified a different amino acid change at the same position (Gly60Val) as likely pathogenic. However, the Grantham’s distance for glycine-to-serine is less (56) than for glycine-to-valine (109), so PM5_Supporting is not met.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
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
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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