Variant: NM_001034853.2(RPGR):c.779-1G>A

CA226446

98802 (ClinVar)

Gene: RPGR

Condition: RPGR-related retinopathy

Inheritance Mode: X-linked inheritance (dominant (HP:0001423))

UUID: 0608a368-77e4-4bde-8685-a139500ec1a9

Approved on: 2025-05-20

Published on: 2025-05-21

HGVS expressions

NM_001034853.2:c.779-1G>A
NM_001034853.2(RPGR):c.779-1G>A
NC_000023.11:g.38304791C>T
CM000685.2:g.38304791C>T
NC_000023.10:g.38164044C>T
CM000685.1:g.38164044C>T
NC_000023.9:g.38048988C>T
NG_009553.1:g.27745G>A
ENST00000642170.1:n.1189-3420G>A
ENST00000642373.1:c.*358-1G>A
ENST00000642395.2:c.779-1G>A
ENST00000642558.1:c.686-1G>A
ENST00000642739.1:c.779-1G>A
ENST00000644238.1:c.779-1G>A
ENST00000644337.1:c.779-1G>A
ENST00000645032.1:c.779-1G>A
ENST00000645124.1:c.779-1G>A
ENST00000646020.1:c.779-1G>A
ENST00000647261.1:c.779-1G>A
ENST00000318842.11:c.779-1G>A
ENST00000339363.7:c.779-1G>A
ENST00000378505.6:c.779-1G>A
ENST00000465127.1:c.172-361330C>T
ENST00000474584.5:c.779-1G>A
ENST00000482855.5:c.779-1G>A
ENST00000494841.1:n.41G>A
NM_000328.2:c.779-1G>A
NM_001034853.1:c.779-1G>A
NM_001367245.1:c.776-1G>A
NM_001367246.1:c.779-1G>A
NM_001367247.1:c.779-1G>A
NM_001367248.1:c.809-1G>A
NM_001367249.1:c.776-1G>A
NM_001367250.1:c.776-1G>A
NM_001367251.1:c.779-1G>A
NR_159803.1:n.921-1G>A
NR_159804.1:n.830-1G>A
NR_159805.1:n.921-1G>A
NR_159806.1:n.921-1G>A
NR_159807.1:n.921-1G>A
NR_159808.1:n.1189-3420G>A
NM_000328.3:c.779-1G>A

Pathogenic

• Met criteria codes: PP4 PP1 PM2_Supporting PVS1

• Not Met criteria codes: PS4 PP3

Expert Panel

X-linked Inherited Retinal Disease VCEP

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

Evidence submitted by expert panel

X-linked Inherited Retinal Disease VCEP

NM_001034853.2(RPGR):c.779-1G>A is a variant disrupting a canonical splice site in intron 7 that is predicted to trigger in-frame skipping of exon 8, encoding a critical domain in the RPGR gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 1 affected meiosis from 1 family, with mother and son both affected (PP1; PMID: 21857984). This variant has been reported in at least 2 probands (PMID: 14564670, PMID: 21857984), only one of whom has been described in detail, so that PS4_Supporting is not met. One proband harboring this variant exhibits a phenotype including rod involvement relatively greater than cone involvement (1 pt), a delayed or milder phenotype in females (1 pt), and a family history showing no male-to-male transmission ( 2 pts), which together are specific for RPGR-related retinopathy (4 points, PP4). 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; PVS1, PM2_supporting, PP1, and PP4. (date of approval 05/16/2025).

Met criteria codes

• PP4: At least one proband harboring this variant exhibits a phenotype including rod involvement relatively greater than cone involvement (1 pt), a delayed or milder phenotype in females (1 pt), and the pedigree shows no male-to-male transmission ( 2 pts), which together are specific for RPGR-related recessive retinopathy (4 points, PP4).
• PP1: The variant has been reported to segregate with retinal dystrophy through at least 1 affected meiosis from 1 family, with mother and son both affected carriers (PP1; PMID: 21857984).
• PM2_Supporting: This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting).
• PVS1: This variant disrupts a canonical splice site in intron 7 which is predicted to trigger in-frame skipping of exon 8, encoding a critical domain in the RPGR gene in which loss-of-function is an established mechanism of disease (PVS1).

Not Met criteria codes

• PS4: This variant has been reported in at least 2 probands, one of whom meets the PS4 requirement of some functional vision impairment in affected males by age 30 and/or decreased or absent cone and/or rod ERG responses (PMID: 14564670, PMID: 21857984). However, this proband has already been counted for PP4 and so PS4_Supporting is not met.
• PP3: The splicing impact predictor SpliceAI gives a score of 0.91 (acceptor loss, -1bp), which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.5 and predicts a damaging impact on splicing (PP3). PVS1 code was applied for this variant, hence, the PP3 code could not be used.