Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001034853.2(RPGR):c.730A>T (p.Lys244Ter)

CA226439

98796 (ClinVar)

Gene: RPGR (HGNC:6103)

Condition: RPGR-related retinopathy (MONDO:0100437)

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

UUID: dd0abccb-401d-44de-a528-3064d41dac6e

Approved on: 2025-05-20

Published on: 2025-05-20

HGVS expressions

NM_001034853.2(RPGR):c.730A>T (p.Lys244Ter)

NM_001034853.2:c.730A>T

NC_000023.11:g.38310663T>A

CM000685.2:g.38310663T>A

NC_000023.10:g.38169916T>A

CM000685.1:g.38169916T>A

NC_000023.9:g.38054860T>A

NG_009553.1:g.21873A>T

ENST00000642170.1:n.1140A>T

ENST00000642373.1:c.*309A>T

ENST00000642395.2:c.730A>T

ENST00000642558.1:c.637A>T

ENST00000642739.1:c.730A>T

ENST00000644238.1:c.730A>T

ENST00000644337.1:c.730A>T

ENST00000645032.1:c.730A>T

ENST00000645124.1:c.730A>T

ENST00000646020.1:c.730A>T

ENST00000647261.1:c.730A>T

ENST00000318842.11:c.730A>T

ENST00000339363.7:c.730A>T

ENST00000378505.6:c.730A>T

ENST00000465127.1:c.172-355458T>A

ENST00000474584.5:c.730A>T

ENST00000482855.5:c.730A>T

NM_000328.2:c.730A>T

NM_001034853.1:c.730A>T

NM_001367245.1:c.727A>T

NM_001367246.1:c.730A>T

NM_001367247.1:c.730A>T

NM_001367248.1:c.760A>T

NM_001367249.1:c.727A>T

NM_001367250.1:c.727A>T

NM_001367251.1:c.730A>T

NR_159803.1:n.872A>T

NR_159804.1:n.781A>T

NR_159805.1:n.872A>T

NR_159806.1:n.872A>T

NR_159807.1:n.872A>T

NR_159808.1:n.1140A>T

NM_000328.3:c.730A>T

Pathogenic

PM2_Supporting PP4 PVS1 PP1_Moderate

Evidence Links 0

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

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.730A>T (p.Lys244Ter) is a nonsense variant that introduces a premature stop codon into exon 7 of 15, and is predicted to lead to nonsense-mediated decay in the RPGR gene in which loss-of-function is an established disease mechanism (PVS1, PMID: 36445968). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family pedigree consistent with X-linked inheritance (2 points), night blindness (0.5 points), delayed or milder phenotype in females (1 point), rod involvement relatively greater than cone involvement (1 point), and peripheral visual field constriction (0.5 points), which together are specific for RPGR-related retinopathy (5 points, PMIDs: 11180598, 21857984, PP4). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from 1 family (PP1_Moderate). In summary, this variant meets the criteria to be 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_Moderate, and PP4. (date of approval 05/16/2025).

PM2_Supporting

This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting).

PP4

At least one proband harboring this variant exhibits a phenotype including a family pedigree consistent with X-linked inheritance (2 points), night blindness (0.5 points), delayed or milder phenotype in females (1 point), rod involvement relatively greater than cone involvement (1 point), and peripheral visual field constriction (0.5 points), which together are specific for RPGR-related recessive retinopathy (5 points, PMID: 11180598, PP4).

PVS1

This is a nonsense variant that introduces a premature stop codon between amino acids 1-1132 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper function of RPGR (PVS1, PMID: 36445968).

PP1_Moderate

The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from 1 family (PP1_Moderate).

Curation History

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