ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.675C>G (p.Ile225Met)

gnomAD frequency: 0.00199  dbSNP: rs114379164
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen RCV003765103 SCV004697392 likely benign RPE65-related recessive retinopathy 2024-02-20 reviewed by expert panel curation NM_000329.3(RPE65):c.675C>G is a missense variant that causes substitution of isoleucine with methionine at codon 225. It is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.005741, with 157 alleles / 24964 total alleles in the African/African-American population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). The computational predictor REVEL gives it a score of 0.238, which is below the ClinGen LCA / eoRD VCEP threshold of <0.290 and predicts a non-damaging effect on RPE65 function. The splicing impact predictor SpliceAI gives a delta score of 0.17 for acceptor loss, which is between the ClinGen LCA / eoRD VCEP recommended thresholds of >0.2 (PP3) and <0.1 (BP4) and does not strongly predict an impact on splicing, so neither PP3 nor BP4 is met. 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).
Eurofins Ntd Llc (ga) RCV000179752 SCV000232051 benign not specified 2014-10-07 criteria provided, single submitter clinical testing
Invitae RCV000950898 SCV001097240 likely benign Leber congenital amaurosis 2; Retinitis pigmentosa 20 2024-01-30 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003907629 SCV004723824 benign RPE65-related condition 2020-07-06 criteria provided, single submitter clinical testing This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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