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

gnomAD frequency: 0.00103  dbSNP: rs61752878

Total submissions: 13

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
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-08-01	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
PreventionGenetics, part of Exact Sciences	RCV004732543	SCV005352246	benign	RPE65-related disorder	2024-09-10	no assertion criteria provided	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).