ClinVar Miner

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

gnomAD frequency: 0.00054  dbSNP: rs149916178
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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 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 2024-03-01 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

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