Variant: NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser)

CA226472

13118 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: a12475a1-7bae-4034-b8bc-f41373cc8110

HGVS expressions

NM_000329.3:c.1022T>C
NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser)
NC_000001.11:g.68438293A>G
CM000663.2:g.68438293A>G
NC_000001.10:g.68903976A>G
CM000663.1:g.68903976A>G
NC_000001.9:g.68676564A>G
NG_008472.1:g.16667T>C
NG_008472.2:g.16667T>C
ENST00000262340.6:c.1022T>C
ENST00000262340.5:c.1022T>C
NM_000329.2:c.1022T>C

Pathogenic

• Met criteria codes: PP3_Moderate PP4_Moderate PM2_Supporting PP1_Strong 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

The NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) missense variant replaces the leucine at position 341 with serine and has been reported in several patients. At least one patient (analyzed on a 100+ retinal dystrophy gene panel testing (2 pt) in PMID: 23847139) who displayed a non-detectable ERG (2 pt), visual acuity 20/400 OD and OS (1 pt), visual field of central island only (1 pt), nystagmus (1 pt), nyctalopia (1 pt), and no pigment in peripheral retina, which is highly specific for RPE65 retinopathy (PP4_Moderate). One patient was compound heterozygous for this variant and a pathogenic pathogenic variant (c.1205_1206insCCTG classified Pathogenic by the LCA/eoRD VCEP) confirmed in trans by parental testing (PMID: 9501220) and two probands were homozygous for the variant (PMID: 9501220, PMID: 15837919) (PM3_strong). The variant has been reported to segregate with RPE65 retinopathy (confirmed by absent or severely decreased rod electroretinogram response) in the proband plus 3 affected family members, all with the compound heterozygous genotype of Leu341Ser and c.1205_1206insCCTG variants. (PP1_strong; PMID: 9501220). The computational predictor REVEL gives a score of 0.988 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is absent from gnomAD v2.1.1 and has a Grpmax Filtering AF of 0.00005290 in gnomAD v.3.1.2 (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: PP1_strong, PM3_strong, PP3_Moderate, PP4_Moderate, PM2_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 0.88, which is above the ClinGen LCA/eoRP VCEP threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate).
• PP4_Moderate: At least one patient (analyzed on a 100+ retinal dystrophy gene panel testing in PMID: 23847139, 2 pt) with this variant displayed a non-detectable rod ERG (required, 1 pt), non-detectable cone ERG (1 pt), visual acuity 20/400 OD and OS (1 pt), visual field of central island only (1 pt), nystagmus (1 pt), nyctalopia (required, 1 pt), and no pigment in peripheral retina, which is highly specific for RPE65 retinopathy (PP4_Moderate).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 and has a Popmax Filtering AF of 0.00005290 in gnomAD v.3.1.2., which is lower than the ClinGen LCA / eoRD threshold (<0.0002) for this criterion (PM2_Supporting).
• PP1_Strong: The variant has been reported to segregate with RPE65 retinopathy (confirmed by absent or severely decreased rod electroretinogram response) in the proband plus 3 affected family members, all with the compound heterozygous genotype with Leu341Ser and c.1205_1206insCCTG variants. (PP1_strong; PMID: 9501220).
• PM3_Strong: This variant has been detected in at least 3 probands with RPE65 retinopathy. One was compound heterozygous for this variant and a pathogenic variant (c.1205_1206insCCTG (p.Trp402CysfsTer6)) classified Pathogenic by the LCA/eoRD VCEP) confirmed in trans by parental testing. (PMID: 9501220; 1pt). Two probands were homozygous for the variant (PMID: 9501220, PMID: 15837919; 1pt). All three probands had the required phenotype of no detectable rod ERGs. Total points: 2pt (PM3_strong). Other cases were not considered to avoid circularity.

Approved on: 2024-02-20

Published on: 2024-02-20