ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.394G>A (p.Ala132Thr)

gnomAD frequency: 0.00103  dbSNP: rs61752878
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Total submissions: 12
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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 RCV003460469 SCV004190214 benign RPE65-related recessive retinopathy 2023-12-22 reviewed by expert panel curation 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).
GeneDx RCV000085196 SCV000565494 likely benign not provided 2018-02-05 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 18722466, 21931134, 11095629, 16150724, 24066033, 9501220, 27535533, 26355662, 26626312)
Counsyl RCV000665910 SCV000790116 likely benign Leber congenital amaurosis 2; Retinitis pigmentosa 20 2017-03-06 criteria provided, single submitter clinical testing
Invitae RCV000665910 SCV001091443 benign Leber congenital amaurosis 2; Retinitis pigmentosa 20 2024-01-31 criteria provided, single submitter clinical testing
Mendelics RCV000986331 SCV001135304 benign Leber congenital amaurosis 2 2023-08-22 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000986331 SCV001435229 likely benign Leber congenital amaurosis 2 criteria provided, single submitter research 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.
Genome-Nilou Lab RCV000986331 SCV001737261 likely benign Leber congenital amaurosis 2 2021-06-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265555 SCV002547977 likely benign not specified 2022-05-03 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000085196 SCV003916464 benign not provided 2024-04-01 criteria provided, single submitter clinical testing RPE65: BS1, BS2
OMIM RCV000013998 SCV000034245 uncertain significance Retinitis pigmentosa 20 1998-03-17 no assertion criteria provided literature only
Retina International RCV000085196 SCV000117333 not provided not provided no assertion provided not provided
Natera, Inc. RCV001278137 SCV001465133 uncertain significance Leber congenital amaurosis 2020-04-03 no assertion criteria provided clinical testing

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