Variant: NM_001034853.2(RPGR):c.968G>A (p.Arg323His)

CA412740347

1317013 (ClinVar)

Gene: RPGR

Condition: RPGR-related retinopathy

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

UUID: c3ff950a-eb6f-44e9-befc-1a69b8162ba9

Approved on: 2025-05-20

Published on: 2025-05-20

HGVS expressions

NM_001034853.2:c.968G>A
NM_001034853.2(RPGR):c.968G>A (p.Arg323His)
NC_000023.11:g.38301338C>T
CM000685.2:g.38301338C>T
NC_000023.10:g.38160591C>T
CM000685.1:g.38160591C>T
NC_000023.9:g.38045535C>T
NG_009553.1:g.31198G>A
ENST00000494707.6:c.172G>A
ENST00000642170.1:n.1222G>A
ENST00000642395.2:c.968G>A
ENST00000642558.1:c.875G>A
ENST00000642739.1:c.968G>A
ENST00000644238.1:c.968G>A
ENST00000644337.1:c.968G>A
ENST00000645032.1:c.968G>A
ENST00000645124.1:c.968G>A
ENST00000646020.1:c.1028G>A
ENST00000318842.11:c.968G>A
ENST00000339363.7:c.968G>A
ENST00000378505.6:c.968G>A
ENST00000464437.1:c.34G>A
ENST00000465127.1:c.172-364783C>T
ENST00000474584.5:c.968G>A
ENST00000482855.5:c.968G>A
ENST00000494841.1:n.231G>A
NM_000328.2:c.968G>A
NM_001034853.1:c.968G>A
NM_001367245.1:c.965G>A
NM_001367246.1:c.968G>A
NM_001367247.1:c.968G>A
NM_001367248.1:c.998G>A
NM_001367249.1:c.965G>A
NM_001367250.1:c.965G>A
NM_001367251.1:c.968G>A
NR_159803.1:n.1170G>A
NR_159804.1:n.1019G>A
NR_159805.1:n.1110G>A
NR_159806.1:n.1110G>A
NR_159807.1:n.1110G>A
NR_159808.1:n.1222G>A
NM_000328.3:c.968G>A

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting

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.968G>A (p.Arg323His) is a missense variant encoding substitution of arginine with histidine at amino acid 323. The variant is present in ClinVar but has not yet been reported in published probands. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000002553 among hemizygous individuals, with 1 variant allele / 391,742 total alleles, which is lower than the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.0000005 (PM2_Supporting). The computational predictor REVEL gives a score of 0.693, which is between the ClinGen X-linked IRD VCEP threshold of 0644 to 0.773 and predicts a damaging effect on RPGR function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict disruption of RPGR splicing. In summary, this variant meets the criteria to be 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_supporting. (date of approval 05/16/2025).

Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.693, which is between the ClinGen X-linked IRD VCEP threshold of 0644 to 0.773 and predicts a damaging effect on RPGR function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.00 for to all types of changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing.
• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at a frequency of 0.000002553 among hemizygous individuals, with 1 variant alleles / 391742 total alleles, which is lower than the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.0000005 (PM2_Supporting).