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NM_000329.3(RPE65):c.675C>G (p.Ile225Met) AND RPE65-related recessive retinopathy

Germline classification:
Likely benign (1 submission)
Last evaluated:
Feb 20, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003765103.1

Allele description [Variation Report for NM_000329.3(RPE65):c.675C>G (p.Ile225Met)]

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

Gene:
RPE65:retinoid isomerohydrolase RPE65 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p31.3
Genomic location:
Preferred name:
NM_000329.3(RPE65):c.675C>G (p.Ile225Met)
Other names:
NM_000329.3(RPE65):c.675C>G; p.Ile225Met
HGVS:
  • NC_000001.11:g.68439611G>C
  • NG_008472.2:g.15349C>G
  • NM_000329.3:c.675C>GMANE SELECT
  • NP_000320.1:p.Ile225Met
  • NC_000001.10:g.68905294G>C
  • NG_008472.1:g.15349C>G
  • NM_000329.2:c.675C>G
Protein change:
I225M
Links:
dbSNP: rs114379164
NCBI 1000 Genomes Browser:
rs114379164
Molecular consequence:
  • NM_000329.3:c.675C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
RPE65-related recessive retinopathy
Synonyms:
Recessive RPE65 retinopathy
Identifiers:
MONDO: MONDO:0100368; MedGen: CN305526

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004697392ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen LCAeoRD ACMG Specifications RPE65 V1.0.0)		Likely Benign
(Feb 20, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen, SCV004697392.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 26, 2024