ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.881A>C (p.Lys294Thr)

gnomAD frequency: 0.00232  dbSNP: rs61752901
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
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 RCV003764755 SCV004697393 likely benign RPE65-related recessive retinopathy 2024-02-20 reviewed by expert panel curation NM_000329.3(RPE65):c.881A>C is a missense variant that causes substitution of lysine with threonine at position 294. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.03554, with 1312 alleles / 35390 total alleles in the Admixed American population (with 33 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the heterozygous state (PMID: 19431183) with the NM_000329.3(RPE65):c.1078G>C (p.Ala360Pro) variant in trans and a 22-bp deletion within exon 12 in cis (PMID: 19431183). However, the proband was not counted for the PM3 or BP2 codes because the other two variants have not yet been classified by the ClinGen LCA / eoRD VCEP. The meta-predictor REVEL gives a score of 0.974, which is above the ClinGen LCA/eoRP VCEP PP3 threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 16%-68% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is between the ClinGen LCA / eoRD VCEP thresholds of <10% activity (PS3_Supporting) and >50% activity (BS3_Supporting), so neither functional study code is met (PMID: 16150724, PMID: 19431183). Another missense variant in the same codon, NM_000329.2; c.880A>G, (p.Lys294Glu), has been observed in a proband with early-onset severe retinal dystrophy (VCEP member-provided data), but has been classified as a variant of uncertain significance for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP, so the PM5_Supporting code is not met. In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BA1 and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Eurofins Ntd Llc (ga) RCV000078655 SCV000110511 benign not specified 2013-10-08 criteria provided, single submitter clinical testing
GeneDx RCV000078655 SCV000514411 benign not specified 2016-12-30 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV000552728 SCV000644186 benign Leber congenital amaurosis 2; Retinitis pigmentosa 20 2024-02-01 criteria provided, single submitter clinical testing
Counsyl RCV000552728 SCV000790166 likely benign Leber congenital amaurosis 2; Retinitis pigmentosa 20 2017-03-07 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001097019 SCV001253270 benign Leber congenital amaurosis 2 2017-04-28 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina RCV001097020 SCV001253271 benign Retinitis pigmentosa 2017-04-28 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000078655 SCV002547973 likely benign not specified 2022-05-03 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002483132 SCV002803730 likely benign Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement 2021-08-16 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV000085227 SCV005258573 likely benign not provided criteria provided, single submitter not provided
Retina International RCV000085227 SCV000117364 not provided not provided no assertion provided not provided
Natera, Inc. RCV001275283 SCV001460283 benign Leber congenital amaurosis 2020-06-18 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.