Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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 |
RCV000078655 | SCV000110511 | benign | not specified | 2013-10-08 | criteria provided, single submitter | clinical testing | |
Gene |
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. |
Invitae | 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, |
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, |
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, |
RCV000078655 | SCV002547973 | likely benign | not specified | 2022-05-03 | criteria provided, single submitter | clinical testing | |
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 | |
Retina International | RCV000085227 | SCV000117364 | not provided | not provided | no assertion provided | not provided | ||
Natera, |
RCV001275283 | SCV001460283 | benign | Leber congenital amaurosis | 2020-06-18 | no assertion criteria provided | clinical testing |