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Variant: NM_000329.3(RPE65):c.419G>A (p.Gly140Glu)

CA340747862

467827 (ClinVar)

Gene: RPE65
Condition: RPE65-related recessive retinopathy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: aa8a7955-4499-4f72-b2ec-e1e2f9783515
Approved on: 2024-02-01
Published on: 2024-02-01

HGVS expressions

NM_000329.3:c.419G>A
NM_000329.3(RPE65):c.419G>A (p.Gly140Glu)
NC_000001.11:g.68444607C>T
CM000663.2:g.68444607C>T
NC_000001.10:g.68910290C>T
CM000663.1:g.68910290C>T
NC_000001.9:g.68682878C>T
NG_008472.1:g.10353G>A
NG_008472.2:g.10353G>A
ENST00000262340.6:c.419G>A
ENST00000262340.5:c.419G>A
NM_000329.2:c.419G>A

Likely Pathogenic

Met criteria codes 4
PP3_Moderate PM2_Supporting PP4_Moderate PM3_Strong
Not Met criteria codes 3
BS1 BP4 BA1

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
NM_000329.3(RPE65):c.419G>A is a missense variant causing substitution of glycine by glutamic acid at position 140. 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, PMID: 30870047). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.242G>T (p.Arg81Ile) and NM_000329.3(RPE65):c.1338G>T (p.Arg446Ser) variants confirmed in trans (2 points, PMID: 30870047), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis with Leber congenital amaurosis (0.5 pts) by exome sequencing that did not provide an alternative explanation for visual impairment (2 pts), onset at 1 month of age (1 pt), undetectable ERG responses from rods (0.5 pts) and cones (1 pt), nyctalopia (0.5 pts), reduced visual acuity (1 pt), light gazing (1 pt), RPE mottling (0.5 pts), optic nerve pallor (0.5 pt), nystagmus (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pt), which together are highly specific for RPE65-related recessive retinopathy (10 total points, PMID: 30870047, PP4_Moderate). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00003893, with 5 alleles / 35438 total alleles in the Admixed American 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 0.847, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). 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, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Met criteria codes
PP3_Moderate
The meta-predictor REVEL gives a score of 0.847, which is above the ClinGen LCA/eoRP VCEP PP3 threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate).
PM2_Supporting
The Popmax FIltering AF for this variant in gnomAD 2.1.1 is 0.00003893, which is lower than the ClinGen LCA / eoRD threshold (<0.0002) for this criterion (PM2_Supporting).
PP4_Moderate
This variant has been found by whole exome in a Leber congenital amaurosis patient without another cause of visual impairment (2 pt) with onset at 1 month of age (1 pt), undetectable rod ERG responses (required, 1 pt), nyctalopia (required, 1 pt), reduced visual acuity (1 pt), light gazing (1 pt), RPE mottling (0.5 pts), undetectable cone ERG responses (1 pt), optic nerve pallor (0.5 pt), nystagmus (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pt) (PMID: 30870047, PP4_Moderate).
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 points, PMID: 30870047). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.242G>T (p.Arg81Ile) and NM_000329.3(RPE65):c.1338G>T (p.Arg446Ser) variants confirmed in trans (2 points, PMID: 30870047), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). This variant has also been reported in an additional proband with retinitis pigmentosa who was compound heterozygous with the NM_000329.2(RPE65):c.292_311del (p.Ile98Hisfs) variant confirmed in trans (PMID: 28181551), however phenotypic details were not sufficient for inclusion in this code.
Not Met criteria codes
BS1
The Popmax FIltering AF for this variant in gnomAD 2.1.1 is 0.00003893, which is lower than the ClinGen LCA / eoRD threshold (>0.000816) for this criterion.
BP4
The meta-predictor REVEL gives a score of 0.847, which is above the ClinGen LCA/eoRP VCEP BP4 threshold of <0.3, while SpliceAI does not identify a suspected splicing defect. The computational evidence fails to meet this criterion.
BA1
The Popmax FIltering AF for this variant in gnomAD 2.1.1 is 0.00003893, which is lower than the ClinGen LCA / eoRD threshold (>0.00816) for this criterion.
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