Variant: NM_000329.3(RPE65):c.991_993dup (p.Trp331dup)

CA915941307

658837 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 46897f1e-128e-4306-bdc9-30a657ff909d

Approved on: 2024-02-18

Published on: 2024-02-18

HGVS expressions

NM_000329.3:c.991_993dup
NM_000329.3(RPE65):c.991_993dup (p.Trp331dup)
NC_000001.11:g.68438947_68438949dup
CM000663.2:g.68438947_68438949dup
NC_000001.10:g.68904630_68904632dup
CM000663.1:g.68904630_68904632dup
NC_000001.9:g.68677218_68677220dup
NG_008472.1:g.16011_16013dup
NG_008472.2:g.16011_16013dup
ENST00000262340.6:c.991_993dup
ENST00000262340.5:c.991_993dup
NM_000329.2:c.991_993dup

Likely Pathogenic

• Met criteria codes: PP4 PP1 PM4_Supporting PM2_Supporting PM3_Strong

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

NM_000329.3(RPE65):c.991_993dup is an in-frame insertion variant encoding a duplication of tryptophan 331. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to cause a change in the length of the protein due to an in-frame insertion encoding 1 amino acid in a non-repeat region, with at least one of the neighboring base pairs highly conserved with a PhyloP conservation score of 7.47347 (PM4_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), visual loss (1 pt) before the age of 5 years (1 pt), nystagmus (1 pt), undetectable or significantly reduced electroretinogram responses from rods (0.5 pts) and cones (1 pt), optic disc pallor (0.5 pt), and retinal pigment epithelium mottling (0.5 pts), which together are specific for RPE65-related recessive retinopathy (6 total pts, PMID: 20683928, PP4). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 20683928). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.11+5G>A variant (suspected in trans, VCEP member-provided data), the NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) variant (suspected in trans, PMID: 32032261), or the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) variant (confirmed in trans, PMID: 20683928), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state in one family member and in the compound heterozygous state in the other (PP1; PMID: 20683928). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3_Strong, PM4_Supporting, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PP4: At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), visual loss (1 pt) before the age of 5 years (1 pt), nystagmus (1 pt), undetectable or significantly reduced ERG responses from rods (0.5 pts) and cones (1 pt), optic disc pallor (0.5 pt), and RPE mottling (0.5 pts), which together are specific for RPE65-related recessive retinopathy (6 total pts, PMID: 20683928, PP4).
• PP1: The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state in one family member and in the compound heterozygous state in the other (PP1; PMID: 20683928).
• PM4_Supporting: This variant is predicted to cause a change in the length of the protein due to an in-frame insertion encoding 1 amino acid in a non-repeat region, with at least one of the neighboring base pairs highly conserved with a PhyloP conservation score of 7.47347 (PM4_Supporting).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PM3_Strong: This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 20683928). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.11+5G>A variant (suspected in trans, VCEP member-provided data), the NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) variant (suspected in trans, PMID: 32032261), or the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) variant (confirmed in trans, PMID: 20683928), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). Although two of these cases are related (aunt and niece), the VCEP decided that both should be counted based on their different genotypes.