NM_000329.3:c.394G>A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS3_SupportingBA1
This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.394G>A is a missense variant that replaces alanine with threonine at codon 132. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.01113, with 372 alleles / 30614 total alleles in the South Asian population (with 6 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The computational predictor REVEL gives a score of 0.548, which is above the ClinGen LCA / eoRD VCEP threshold of <0.3 and does not strongly predict a non-damaging effect on RPE65 function. The splicing impact predictor SpliceAI gives a score of 0.03 for splice acceptor loss, 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 50% enzymatic activity in an isomerohydrolase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves] normal protein function (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, BS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226547/MONDO:0100368/120
Frequency
Consequence
NM_000329.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00147 AC: 224AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00294 AC: 739AN: 251320Hom.: 9 AF XY: 0.00352 AC XY: 478AN XY: 135880
GnomAD4 exome AF: 0.00168 AC: 2456AN: 1461858Hom.: 26 Cov.: 32 AF XY: 0.00200 AC XY: 1451AN XY: 727232
GnomAD4 genome AF: 0.00145 AC: 221AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.00150 AC XY: 112AN XY: 74446
ClinVar
Submissions by phenotype
Leber congenital amaurosis 2 Benign:3
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The p.Ala132Thr variant in RPE65 has been identified in 2 homozygous siblings from 1 family with retinitis pigmentosa (PMID: 9501220), and in the heterozygous state in 2 unrelated individuals with retinitis pigmentosa from India and Dubai respectively (PMID: 24066033, 24265693). In vitro functional studies provide some evidence that the p.Ala132Thr variant may slightly impact protein function (PMID: 16150724). However, these types of assays may not accurately represent biological function and this variant has been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive retinitis pigmentosa. -
not provided Benign:2Other:1
RPE65: BS1, BS2 -
This variant is associated with the following publications: (PMID: 18722466, 21931134, 11095629, 16150724, 24066033, 9501220, 27535533, 26355662, 26626312) -
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Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 Benign:2
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Leber congenital amaurosis Uncertain:1
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Retinitis pigmentosa 20 Uncertain:1
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not specified Benign:1
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RPE65-related disorder Benign:1
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). -
RPE65-related recessive retinopathy Benign:1
NM_000329.3(RPE65):c.394G>A is a missense variant that replaces alanine with threonine at codon 132. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.01113, with 372 alleles / 30614 total alleles in the South Asian population (with 6 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The computational predictor REVEL gives a score of 0.548, which is above the ClinGen LCA / eoRD VCEP threshold of <0.3 and does not strongly predict a non-damaging effect on RPE65 function. The splicing impact predictor SpliceAI gives a score of 0.03 for splice acceptor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of greater than or equal to 0.2 and does not strongly predict an impact on splicing. The variant exhibited 50% enzymatic activity in an isomerohydrolase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves] normal protein function (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, BS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). -
Retinal dystrophy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at