Submissions for variant NM_000329.3(RPE65):c.886dup (p.Arg296fs)

dbSNP: rs746127684

Total submissions: 4

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	RCV003462987	SCV004190213	pathogenic	RPE65-related recessive retinopathy	2023-12-22	reviewed by expert panel	curation	NM_000329.3(RPE65):c.886dup (p.Arg296fs) is a frameshift variant that introduces a premature stop codon into exon 9 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). At least 3 affected patients have been reported harboring this variant (PMID: 20683928, PMID: 28838317, PMID: 26906952). 1 affected patient harbors p.Arg296fs confirmed in trans with c.11+5G>A, which has been classified Pathogenic by this VCEP (PMID: 20683928, ClinVar ID: 98825, PM3), while a second affected patient harbors this variant in the homozygous state (PMID: 28838317). At least 1 of these patients harboring the variant exhibits an undetectable electroretinogram responses from rods (0.5 pts) and cones (1 pt) with infantile onset (1 pt), nystagmus (1 pt), and reduced visual acuity (1 pt), which together are specific for RPE65-related recessive retinopathy (4.5 pts total, PMID: 20683928, PP4). The GrpMax Filtering AF for this variant in gnomAD v2.1.1 is 0.00001082 in the South Asian population, which 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, PP4, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001383023	SCV001582031	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2023-03-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg296Lysfs*7) 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). This variant is present in population databases (rs779023449, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with retinal dystrophy (PMID: 20683928, 26906952, 28838317). ClinVar contains an entry for this variant (Variation ID: 1070755). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV003883623	SCV004703497	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	RPE65: PVS1, PM3:Strong, PM2
Fulgent Genetics, Fulgent Genetics	RCV005023138	SCV005660967	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement	2024-05-31	criteria provided, single submitter	clinical testing