Variant: NM_000329.3(RPE65):c.938A>G (p.His313Arg)

CA340744821

1679125 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 4595da62-656a-482d-b84c-f4d607fb808c

Approved on: 2024-04-22

Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.938A>G
NM_000329.3(RPE65):c.938A>G (p.His313Arg)
NC_000001.11:g.68439002T>C
CM000663.2:g.68439002T>C
NC_000001.10:g.68904685T>C
CM000663.1:g.68904685T>C
NC_000001.9:g.68677273T>C
NG_008472.1:g.15958A>G
NG_008472.2:g.15958A>G
ENST00000262340.6:c.938A>G
ENST00000262340.5:c.938A>G
NM_000329.2:c.938A>G

Pathogenic

• Met criteria codes: PP3_Moderate PM2_Supporting PM3 PM1 PS3_Supporting PP4_Moderate

• Not Met criteria codes: PM5

Expert Panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPE65 Version 1.0.0

Evidence submitted by expert panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

The NM_000329.3(RPE65):c.938A>G (p.His313Arg) variant is a missense substitution at His313, which is located within the active site, a well-characterized functional domain required for enzymatic activity (PM1, PMID: 34492281).The computational predictor REVEL gives a score of 0.964 which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 24849605). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 points), absent ERG (0.5 points), nystagmus (0.5 points) and decreased visual acuity (1 point). This patient showed significant improvement in several measures of dark-adapted vision after gene therapy treatment (8 points). Together these are highly specific for RPE65-related recessive retinopathy (10.5 points, PMID: 19854499, PP4_Moderate). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMIDs: 35129589). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.292_311del(p.Ile98Hisfs*26) variant suspected in trans (0.5 points) and at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Tyr386 variant suspected in trans (0.5 points) (PMID: 35129589), which were both previously classified pathogenic by the ClinGen LCA/eoRD VCEP. (1.5 total points, PM3).This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.000002280, with 4 alleles/418086 total alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP3_Moderate, PP4_Moderate, PM1, PM3, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023)

Met criteria codes

• PP3_Moderate: The computational predictor REVEL gives a score of 0.964 which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate).
• PM2_Supporting: This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.000002280, with 4 alleles / 418086 total alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).
• PM3: This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMIDs: 35129589). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.292_311del(p.Ile98Hisfs*26) variant suspected in trans (0.5 points) and at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Tyr386 variant suspected in trans (0.5 points) (PMID: 35129589), which were both previously classified pathogenic by the ClinGen LCA/eoRD VCEP. (1.5 total points, PM3).
• PM1: This variant is a missense substitution at His313, which is located within the active site, a well-characterized functional domain required for enzymatic activity (PM1, PMID: 34492281).
• PS3_Supporting: The variant exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 24849605)
• PP4_Moderate: At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pt), absent ERG (0.5 pt), nystagmus (0.5 pt), and decreased visual acuity (1 pt). Patient showed significant improvement in several measures of dark-adapted vision after gene therapy treatment (8 pt). Together these are highly specific for RPE65-related recessive retinopathy (10.5 points, PMID: 19854499, PP4_Moderate)

Not Met criteria codes

• PM5: Two other amino acid substitutions at position 313 have been observed (p.His313Pro, p.His313Gln (ClinVar ID 1180616 and PMID 24066033) but have not yet been classified by the LCA/eoRD VCEP.