ClinVar Miner

Submissions for variant NM_000329.2(RPE65):c.292_311del (p.Ile98Hisfs)

dbSNP: rs62642583
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Total submissions: 9
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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 RCV003764792 SCV004697399 pathogenic RPE65-related recessive retinopathy 2024-02-20 reviewed by expert panel curation NM_000329.2(RPE65):c.292_311del (p.Ile98Hisfs) is a deletion variant in exon 4 of 14 that causes a frameshift and introduces a premature stop after 26 codons. This frameshift is predicted to trigger nonsense mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). A number of affected patients have been reported harboring this variant, including at least 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 30870047, PM3). This variant has a Grpmax filtering allele frequency of 0.0001565 (10/34580) in the Latino / Admixed American population in gnomAD v2.1.1 (with no homozygotes). This allele frequency is lower than the ClinGen LCA/eoRD VCEP threshold (<0.0002) (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM3, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Cytogenetics and Genomics Laboratory, Medical University of South Carolina RCV000754976 SCV000803386 pathogenic Leber congenital amaurosis 2018-06-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV000815030 SCV000955471 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2023-06-25 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 98860). This premature translational stop signal has been observed in individuals with RPE65-related conditions (PMID: 10766140, 28181551). This variant is present in population databases (rs767212885, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Ile98Hisfs*26) in the RPE65 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220, 9843205, 18632300).
Mendelics RCV000986333 SCV001135306 pathogenic Leber congenital amaurosis 2 2019-05-28 criteria provided, single submitter clinical testing
GeneDx RCV000085189 SCV001817432 pathogenic not provided 2020-01-13 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32865313, 31589614, 30870047, 10766140, 28181551)
3billion RCV000986333 SCV002572805 pathogenic Leber congenital amaurosis 2 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 11462243). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000098860 / PMID: 10766140 , 32347917 , 35129589). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics RCV000986333 SCV004209246 pathogenic Leber congenital amaurosis 2 2023-08-10 criteria provided, single submitter clinical testing
Retina International RCV000085189 SCV000117326 not provided not provided no assertion provided not provided
Natera, Inc. RCV000754976 SCV002092775 pathogenic Leber congenital amaurosis 2021-01-06 no assertion criteria provided clinical testing

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