Submissions for variant NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly)

dbSNP: rs1571158279

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Farrar Lab, Smurfit Institute of Genetics, Trinity College Dublin	RCV001034696	SCV001021978	pathogenic	RPE65-related disorder	2019-12-10	criteria provided, single submitter	clinical testing	The Asp477Gly variant has been previously reported in several publications (Bowne 2011, PMID: 21654732; Hull 2016, PMID: 27307694). Functional analysis in animal models of the variant has also displayed a similar pathology (Shin 2017, PMID: 28041994). This missense mutation appears to result in aberrant RNA splicing (Li 2019, PMID: 30628748). The phenotype is an unusual retinitis pigmentosa, often presenting as a phenocopy of choroideremia. The inheritance pattern is autosomal dominant with a variable age of onset. The variant is absent from large population databases (gnomAD). In the Irish population there are currently 23 individuals confirmed affected with this genotype from 7 different pedigrees. Based on population, cosegregation and functional data, we interpret this variant as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068036	SCV001233124	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2024-07-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 477 of the RPE65 protein (p.Asp477Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant retinal dystrophy with choroidal involvement (PMID: 21654732, 27307694, 29947567). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 750796). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RPE65 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RPE65 function (PMID: 21654732, 28041994, 29659842, 30628748). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074701	SCV001240294	pathogenic	Retinal dystrophy	2019-04-03	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376263	SCV001573342	pathogenic	Retinitis pigmentosa 20	2021-04-08	criteria provided, single submitter	research	The RPE65 c.1430A>G variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PP1-S. Based on this evidence we have classified this variant as Pathogenic.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV002279647	SCV002564458	pathogenic	Neurodevelopmental disorder	2021-12-16	criteria provided, single submitter	clinical testing
GeneDx	RCV003117646	SCV003798948	likely pathogenic	not provided	2023-02-02	criteria provided, single submitter	clinical testing	Reported to co-segregate with a late-onset form of autosomal dominant RP (adRP) with choroidal involvement (Kiang et al., 2020; Jauregui et al., 2018; Doucette et al., 2021; Browne et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Published functional studies suggest this variant has a dominant negative effect and may cause aberrant splicing, however additional studies are needed to validate the functional effect of this variant in vivo (Li et al., 2019; Wu et al., 2022); This variant is associated with the following publications: (PMID: 27307694, 28041994, 32581362, 33261050, 32426524, 33512609, 30628748, 33776059, 29659842, 21654732, 29947567, 32014860, 35271391)
OMIM	RCV000927801	SCV001073396	pathogenic	Retinitis pigmentosa 87 with choroidal involvement	2020-04-01	no assertion criteria provided	literature only