Variant: NM_000329.3(RPE65):c.295G>A (p.Val99Ile)

CA902549

789504 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: cef52d99-7f6d-4daf-881f-71fbbc443327

Approved on: 2024-02-19

Published on: 2024-02-19

HGVS expressions

NM_000329.3:c.295G>A
NM_000329.3(RPE65):c.295G>A (p.Val99Ile)
NC_000001.11:g.68444834C>T
CM000663.2:g.68444834C>T
NC_000001.10:g.68910517C>T
CM000663.1:g.68910517C>T
NC_000001.9:g.68683105C>T
NG_008472.1:g.10126G>A
NG_008472.2:g.10126G>A
ENST00000262340.6:c.295G>A
ENST00000262340.5:c.295G>A
NM_000329.2:c.295G>A

Likely Benign

• Met criteria codes: BS1

• Not Met criteria codes: PP4 PP3 PM3 BP4

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.295G>A is a missense variant causing substitution of valine with isoleucine at position 99. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.002650, with 68 alleles / 19954 total alleles in the East Asian population (with 2 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), extinguished electroretinogram responses from rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), peripheral vision loss and (1 pt). However, the proband lacks the second variant required to apply the PP4 code. This variant has been reported in at least 4 probands with early-onset severe retinal dystrophy who harbored the variant in the heterozygous state (PMID: 21602930). However, the probands were not counted for PM3 because they lacked the second variant required to apply the code. The computational predictor REVEL gives a score of 0.517, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.10, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BS1. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• BS1: This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.002650, with 68 alleles / 19954 total alleles in the East Asian population (with 2 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1).

Not Met criteria codes

• PP4: At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts), extinguished rod (0.5 pts) and cone (1 pt) ERG responses, nystagmus (1 pt), peripheral vision loss (1 pt), attenuated vessels, and absence of a foveal reflex (5 pts total). However, the proband lacks the second variant required to apply the PP4 code.
• PP3: The computational predictor REVEL gives a score of 0.517, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.10, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.
• PM3: This variant has been reported in at least 4 probands with early-onset severe retinal dystrophy who harbored the variant in the heterozygous state (PMID: 21602930). However, the probands were not counted for PM3 because they lacked the second variant required to apply the code.
• BP4: The computational predictor REVEL gives a score of 0.517, which is above the ClinGen LCA / eoRD VCEP threshold of <0.290 and does not predict a non-damaging effect on RPE65 function. The splicing impact predictor SpliceAI gives a delta score of 0.10, which is above the ClinGen LCA / eoRD VCEP threshold of <0.1 and represents an intermediate prediction of impact on RPE65 splicing.