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.48T>C (p.Phe16=)

CA226554

98871 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ec7a04bb-80b5-4d84-9564-8fe84af2bc08

Approved on: 2024-04-22

Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.48T>C

NM_000329.3(RPE65):c.48T>C (p.Phe16=)

NC_000001.11:g.68448670A>G

CM000663.2:g.68448670A>G

NC_000001.10:g.68914353A>G

CM000663.1:g.68914353A>G

NC_000001.9:g.68686941A>G

NG_008472.1:g.6290T>C

NG_008472.2:g.6290T>C

ENST00000262340.6:c.48T>C

ENST00000262340.5:c.48T>C

NM_000329.2:c.48T>C

Likely Benign

BP7 BP4 BS1

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.48T>C (p.Phe16=) is a synonymous (silent) variant in exon 2. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.001007, with 1250 alleles/1179940 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0008 (BS1). The REVEL score for this variant is 0, which is below the ClinGen LCA/eoRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPE65 function. Additionally, the splicing impact predictor, SpliceAI, gives a score of 0.01, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). 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, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

BP7

The splicing impact predictor SpliceAI gives a score of 0.01, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP7).

BP4

The REVEL score for this variant is 0, which is below the ClinGen LCA/eoRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPE65 function. In addition, the splicing impact predictor SpliceAI gives a score of 0.01, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4).

BS1

This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.001007, with 1250 alleles / 1179940 total alleles in the European non-Finnish population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0008. Additionally, there are two homozygotes in this population. (BS1)

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