Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000329.3(RPE65):c.982C>T (p.Leu328Phe)

CA340744630

556178 (ClinVar)

Gene: RPE65
Condition: RPE65-related recessive retinopathy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 1305bc70-d6b9-423b-be87-64de62a7e96d
Approved on: 2024-12-12
Published on: 2024-12-12

HGVS expressions

NM_000329.3:c.982C>T
NM_000329.3(RPE65):c.982C>T (p.Leu328Phe)
NC_000001.11:g.68438958G>A
CM000663.2:g.68438958G>A
NC_000001.10:g.68904641G>A
CM000663.1:g.68904641G>A
NC_000001.9:g.68677229G>A
NG_008472.1:g.16002C>T
NG_008472.2:g.16002C>T
ENST00000262340.6:c.982C>T
ENST00000262340.5:c.982C>T
NM_000329.2:c.982C>T
More

Likely Pathogenic

Met criteria codes 4
PP4 PP3 PM2_Supporting PM3_Strong

Evidence Links 0

Expert Panel

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP
The NM_000329.3(RPE65):c.982C>T (p.Leu328Phe) variant is a missense variant causing a substitution of leucine with phenylalanine at position 328. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.000003650, with 2/91076 in the South Asian population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.737, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.644 and predicts a damaging effect on RPE65 function (PP3). This variant has been reported in at least 4 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the p.Tyr275Ter variant confirmed in trans (Pathogenic by VCEP, 1 point, PMID: 31630094); the NM_000329.3(RPE65):c.639dup (p.Ala214SerfsTer20) variant suspected in trans (Pathogenic by VCEP, 0.5 pt, PMID: 28393863); the p.Glu254Asp variant suspected in trans (LP by VCEP, 0.25 pt, PMID: 35129589 with additional information presented in ARVO meeting abstract https://iovs.arvojournals.org/article.aspx?articleid=2767855); or the p.Leu447Pro variant confirmed in trans (VUS by VCEP, 0.25 pt, PMID: 38002999), all of which were previously classified as described above by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pt), congenital night blindness (0.5 pt), White/yellow dot deposits (2 pt), previous exome testing that did not provide an alternative explanation for visual impairment (2 pt), and symptomatic onset between birth and 5 years (1 pt), which together are specific for RPE65-related recessive retinopathy (6 points, PMIDs: 31630094, 34830511, PP4). 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, PP3, PP4, PM3_Strong (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 clinical diagnosis of Leber congenital amaurosis (0.5 pt), congenital night blindness (0.5 pt), White/yellow dot deposits (2 pt), previous exome testing that did not provide an alternative explanation for visual impairment (2 pt), and symptomatic onset between birth and 5 years (1 pt), which together are specific for RPE65-related recessive retinopathy (6 points, PMIDs: 31630094, 34830511, PP4).
PP3
The computational predictor REVEL gives a score of 0.737, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.644 and predicts a damaging effect on RPE65 function (PP3).
PM2_Supporting
This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.000003650, with 2/91076 in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).
PM3_Strong
This variant has been reported in at least 4 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the p.Tyr275Ter variant confirmed in trans (Pathogenic by VCEP, 1 point, PMID: 31630094); the NM_000329.3(RPE65):c.639dup (p.Ala214SerfsTer20) variant suspected in trans (Pathogenic by VCEP, 0.5 pt, PMID: 28393863); the p.Glu254Asp variant suspected in trans (LP by VCEP, 0.25 pt, PMID: 35129589 with additional information presented in ARVO meeting abstract https://iovs.arvojournals.org/article.aspx?articleid=2767855); or the p.Leu447Pro variant confirmed in trans (VUS by VCEP, 0.25 pt, PMID: 38002999), all of which were previously classified as described above by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong).
Curation History
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