ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.1301C>T (p.Ala434Val)

gnomAD frequency: 0.02403  dbSNP: rs34627040
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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 RCV003460768 SCV004190218 benign RPE65-related recessive retinopathy 2023-12-22 reviewed by expert panel curation The NM_000329.3(RPE65):c.1301C>T (p.Ala434Val) missense variant that is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.07646, with 1976 alleles / 24962 total alleles in the African / African-American population with 72 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The variant has been reported in at least one patient with retinal dystrophy, however the phenotype is not specific to RPE65 and no second variant was described in trans (PMID: 9501220). Three separate publications on families who carry this variant have reported unaffected individuals who harbor it in homozygous state (PMID: 19431183, PMID: 9501220, PMID: 19920137, BS2). The computational predictor REVEL gives a score of 0.418, which is below the ClinGen LCA / eoRD VCEP threshold of greater than or equal to 0.7 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.14, 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 110% or 55% enzymatic activity in two retinoid isomerase assays relative to the wild-type control, which are higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves normal protein function (PMID: 19431183, 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, BS2, BS3_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Eurofins Ntd Llc (ga) RCV000327489 SCV000342673 benign not specified 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000327489 SCV000514412 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 RCV000539372 SCV000644179 benign Leber congenital amaurosis 2; Retinitis pigmentosa 20 2024-01-31 criteria provided, single submitter clinical testing
Counsyl RCV000539372 SCV000788920 benign Leber congenital amaurosis 2; Retinitis pigmentosa 20 2017-03-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000085162 SCV001159182 benign not provided 2023-10-16 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001096917 SCV001253163 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). 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 RCV001096918 SCV001253164 benign 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000327489 SCV002050877 likely benign not specified 2021-12-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002490739 SCV002804180 benign Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement 2022-04-21 criteria provided, single submitter clinical testing
Retina International RCV000085162 SCV000117299 not provided not provided no assertion provided not provided
Natera, Inc. RCV001273331 SCV001456290 benign Leber congenital amaurosis 2020-09-16 no assertion criteria provided clinical testing

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