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]

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Variant: NM_000329.3(RPE65):c.399T>C (p.Leu133=)

CA226548

98867 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9345e90f-7140-4d29-8392-a6ef51636e74

Approved on: 2024-04-22

Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.399T>C

NM_000329.3(RPE65):c.399T>C (p.Leu133=)

NC_000001.11:g.68444627A>G

CM000663.2:g.68444627A>G

NC_000001.10:g.68910310A>G

CM000663.1:g.68910310A>G

NC_000001.9:g.68682898A>G

NG_008472.1:g.10333T>C

NG_008472.2:g.10333T>C

ENST00000262340.6:c.399T>C

ENST00000262340.5:c.399T>C

NM_000329.2:c.399T>C

Benign

BA1 BP7 BP4

Evidence Links 0

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

NM_000329.3(RPE65):c.399T>C (p.Leu133=) is a synonymous variant located in exon 5. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.02168, with 1732 alleles/75042 total alleles in the African/African-American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). Additionally, there are 20 homozygotes in this population. The splicing impact predictor SpliceAI gives delta scores of 0.07 for acceptor gain and donor gain, which are below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and do not predict an impact on splicing (BP4, BP7). 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, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

BA1

This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.02168, with 1732 alleles/75042 total alleles in the African/African American population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.008. Additionally, there are 20 homozygotes in this population. (BA1)

BP7

The splicing impact predictor SpliceAI gives a delta score of 0.07, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP7).

BP4

There is no REVEL data for this variant. The splicing impact predictor SpliceAI gives a delta score of 0.07, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4).

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