Submissions for variant NM_000329.3(RPE65):c.963T>G (p.Asn321Lys)

gnomAD frequency: 0.00054  dbSNP: rs149916178

Total submissions: 12

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	RCV003460744	SCV004190216	benign	RPE65-related recessive retinopathy	2023-12-22	reviewed by expert panel	curation	The NM_000329.3(RPE65):c.963T>G (p.Asn321Lys) missense variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.03299, with 1063 alleles / 30614 total alleles in the South Asian population with 29 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). This variant has been reported in at least one LCA patient, however the phenotype is not sufficiently specific to RPE65 and no second variant was described in trans, instead two CRB1 variants were identified (PMID: 18055816). The computational predictor REVEL gives a score of 0.215, which is below the ClinGen LCA/eoRD VCEP threshold of <0.3 and predicts no damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). The variant exhibited 127% 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 preserves normal protein function (PMID: 19431183, BS3). 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, BP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Eurofins Ntd Llc (ga)	RCV000078656	SCV000110512	benign	not specified	2013-10-08	criteria provided, single submitter	clinical testing
Invitae	RCV000945854	SCV001091917	benign	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001102426	SCV001259097	likely benign	Leber congenital amaurosis 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001102427	SCV001259098	uncertain significance	Retinitis pigmentosa	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001258234	SCV001435140	benign	Joubert syndrome 9		criteria provided, single submitter	research	The heterozygous p.Asn321Lys variant in RPE65 has been identified in an individual with Leber congenital amaurosis (PMID: 10766140), but has also been identified in >3% of South Asian chromosomes and 18 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Leber congenital amaurosis.
Pars Genome Lab	RCV001102426	SCV001652873	likely benign	Leber congenital amaurosis 2	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000078656	SCV002103454	likely benign	not specified	2022-02-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001727561	SCV004032955	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	RPE65: BS1, BS2
Natera, Inc.	RCV001275282	SCV001460282	benign	Leber congenital amaurosis	2020-04-03	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000078656	SCV001924287	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001727561	SCV001968656	likely benign	not provided		no assertion criteria provided	clinical testing