Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000329.3(RPE65):c.1301C>T (p.Ala434Val)

CA226501

98836 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f70f8917-2432-426c-8fea-58947fe136be

Approved on: 2023-12-22

Published on: 2023-12-22

HGVS expressions

NM_000329.3:c.1301C>T

NM_000329.3(RPE65):c.1301C>T (p.Ala434Val)

NC_000001.11:g.68431319G>A

CM000663.2:g.68431319G>A

NC_000001.10:g.68897002G>A

CM000663.1:g.68897002G>A

NC_000001.9:g.68669590G>A

NG_008472.1:g.23641C>T

NG_008472.2:g.23641C>T

ENST00000262340.6:c.1301C>T

ENST00000262340.5:c.1301C>T

NM_000329.2:c.1301C>T

Benign

BS2 BS3_Supporting BA1

BP4 PS3 PP3

Evidence Links 1

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

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.1301C>T (p.Ala434Val) missense variant that is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.07646, with 1976 alleles / 24962 total alleles in the African / African-American population with 72 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The variant has been reported in at least one patient with retinal dystrophy, however the phenotype is not specific to RPE65 and no second variant was described in trans (PMID: 9501220). Three separate publications on families who carry this variant have reported unaffected individuals who harbor it in homozygous state (PMID: 19431183, PMID: 9501220, PMID: 19920137, BS2). The computational predictor REVEL gives a score of 0.418, which is below the ClinGen LCA / eoRD VCEP threshold of ≥ 0.7 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.14, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. The variant exhibited 110% or 55% enzymatic activity in two retinoid isomerase assays relative to the wild-type control, which are higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves normal protein function (PMID: 19431183, PMID: 16150724, BS3_Supporting). In summary, this variant meets the criteria to be classified as Benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, BS3_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

BS2

In PMID: 19431183, in one family who carried the p.Ala434Val variant, one of the unaffected parents was found to be homozygous for this change. A second homozygous unaffected individual was found in PMID: 9501220, however, age was not specified. An unaffected homozygous individual was also reported in PMID: 19920137. While details are not available to clarify whether these patients are distinct from one another, the three reporting research groups appear to be separate. This criterion requires at least 3 such patients and therefore is met (BS2).

BS3_Supporting

An isomerohydrolase assay performed with the Ala434Val recombinant mutant RPE65 expressed by 293T-LC cells showed isomerohydrolase activity (based on 11-cis-retinol levels measured by HPLC) comparable to wild-type(110%) indicating that this variant does not have a damaging effect on protein function (PMID: 19431183)(BS3). A second isomerohydrolase assay performed with the Ala434Val recombinant mutant RPE65 expressed by 293-F cells showed isomerohydrolase activity (based on 11-cis-retinol levels measured by HPLC) lower than wild-type (55%) indicating that this variant largely preserves normal protein function (PMID: 16150724).

An isomerohydrolase assay performed with the Ala434Val recombinant mutant RPE65 expressed by 293-F cells showed isomerohydrolase activity (based on 11-cis-retinol levels measured by HPLC) lower than wild-type (55%) indicating that this variant has a mildly damaging hypomorphic effect on protein function (Table 1). Many other variants suspected to be pathogenic exhibited less than 2% of wild-type enzymatic activity. PubMed:16150724

BA1

The Popmax Filtering AF for this variant in gnomAD v2.1.1 is 0.07646 (with 72 homozygotes). This allele frequency is higher than the ClinGen LCA/eoRD VCEP threshold (>0.00816) for BA1 and therefore meets this criterion (BA1).

BP4

The meta-predictor REVEL gives a score of 0.418, which is above the ClinGen LCA/eoRD VCEP BP4 threshold of <0.3. The computational splicing predictor SpliceAI predicts that the variant may cause splice donor loss (at -37bp), with a change score of 0.14. The computational evidence fails to meet this criterion.

PS3

Two approved enzymatic assays (PMID: 16150724, PMID: 19431183) estimated the enzymatic activity of this variant at 55% or 110% of the wild-type control, indicating preservation of wild-type activity.

PP3

The meta-predictor REVEL gives a score of 0.418, which is below the ClinGen LCA/eoRD VCEP PP3 threshold of >0.75 and does not predict a damaging effect on RPE65 function (PP3). The computational splicing predictor SpliceAI predicts that the variant may cause splice donor loss (at -37bp), with a change score of 0.14. The computational evidence fails to meet this criterion.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.