Variant: NM_001034853.2(RPGR):c.2057T>A (p.Met686Lys)

Version: 1.0
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CA10385310

1276872 (ClinVar)

Gene: RPGR (HGNC:6103)

Condition: RPGR-related retinopathy

Inheritance Mode: X-linked inheritance

UUID: 61b91eef-87da-47a0-bc00-83a05fe472d0

Approved on: 2025-08-04

Published on: 2025-08-04

HGVS expressions

NM_001034853.2:c.2057T>A
NM_001034853.2(RPGR):c.2057T>A (p.Met686Lys)
NC_000023.11:g.38286942A>T
CM000685.2:g.38286942A>T
NC_000023.10:g.38146195A>T
CM000685.1:g.38146195A>T
NC_000023.9:g.38031139A>T
NG_009553.1:g.45594T>A
ENST00000494707.6:c.953+923T>A
ENST00000642170.1:n.1826+4017T>A
ENST00000642395.2:c.1905+152T>A
ENST00000642739.1:c.1572+4017T>A
ENST00000644238.1:c.1386+4017T>A
ENST00000644337.1:c.1719+152T>A
ENST00000645032.1:c.2057T>A
ENST00000645124.1:c.*101+152T>A
ENST00000646020.1:c.*594+152T>A
ENST00000318842.11:c.1905+152T>A
ENST00000339363.7:c.2520+152T>A
ENST00000378505.6:c.2057T>A
ENST00000465127.1:c.172-379179A>T
ENST00000474584.5:c.*37+4017T>A
ENST00000482855.5:c.1905+152T>A
ENST00000494707.5:c.139+4017T>A
NM_000328.2:c.1905+152T>A
NM_001034853.1:c.2057T>A
NM_001367245.1:c.1902+152T>A
NM_001367246.1:c.1719+152T>A
NM_001367247.1:c.1572+4017T>A
NM_001367248.1:c.1602+4017T>A
NM_001367249.1:c.1569+4017T>A
NM_001367250.1:c.1569+4017T>A
NM_001367251.1:c.1386+4017T>A
NR_159803.1:n.2263+152T>A
NR_159804.1:n.1648+4017T>A
NR_159805.1:n.1714+4017T>A
NR_159806.1:n.1866+152T>A
NR_159807.1:n.1622+4017T>A
NR_159808.1:n.1826+4017T>A
NM_000328.3:c.1905+152T>A

Benign

• Met criteria codes: BP4_Strong BA1

• Not Met criteria codes: BS2 PS4

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.2057T>A (p.Met686Lys) is a missense variant predicted to cause substitution of methionine by lysine at amino acid 686. This variant is present in gnomAD v.4.1.0 at a frequency of 0.002245 among hemizygous individuals, with 874 variant alleles / 389,312 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been observed in at least 3 affected male individuals with features consistent with retinopathy, but was not considered to be the causal variant PMID: 33846575, 24938718). The computational predictor REVEL gives a score of 0.014, which is below the ClinGen X-linked IRD VCEP threshold of < 0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.2 and does not strongly predict an impact on splicing (BP4_Strong). In summary, this variant is classified as benign 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; BA1 and BP4_Strong. (date of approval 05/16/2025).

Met criteria codes

• BP4_Strong: The computational predictor REVEL gives a score of 0.014, which is below the ClinGen X-linked IRD VCEP threshold of < 0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.2 and does not strongly predict an impact on splicing (BP4_Strong).
• BA1: This variant is present in gnomAD v.4.1.0 at a frequency of 0.002245 among hemizygous individuals, with 874 variant alleles / 389,312 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1).

Not Met criteria codes

• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: This variant has been observed in at least 3 affected male individuals with features consistent with retinopathy, but was not considered to be the causal variant PMID: 33846575, 24938718).