Submissions for variant NM_000329.3(RPE65):c.1355T>G (p.Val452Gly)

gnomAD frequency: 0.00002  dbSNP: rs62637004

Total submissions: 7

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	RCV004801914	SCV005423709	likely pathogenic	RPE65-related recessive retinopathy	2024-12-12	reviewed by expert panel	curation	The NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variant is a missense variant in RPE65 causing a substitution of valine with glycine at position 452. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.00001064, with 3/74896 alleles in the African/African American population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.945, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the p.Arg91Trp variant or the c.11+5G>A variant confirmed in trans (2 points, PMID: 9501220; laboratory-provided internal data), which were previously classified pathogenic or likely pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3_Moderate, PM3_Strong (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001304649	SCV001493941	uncertain significance	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine with glycine at codon 452 of the RPE65 protein (p.Val452Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with autosomal recessive retinitis pigmentosa (PMID: 9501220). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 13116). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000085169	SCV001827970	likely pathogenic	not provided	2020-09-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9501220)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114190	SCV003800726	uncertain significance	not specified	2023-01-05	criteria provided, single submitter	clinical testing	Variant summary: RPE65 c.1355T>G (p.Val452Gly) results in a non-conservative amino acid change to a highly conserved residue in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250734 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1355T>G has been reported in the literature in an individual affected with retinitis pigmentosa (Morimura_1998). The individual was reported as compound heterozygous with another known pathogenic missense variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
Fulgent Genetics, Fulgent Genetics	RCV005025051	SCV005660827	likely pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement	2024-06-13	criteria provided, single submitter	clinical testing
OMIM	RCV000013995	SCV000034242	pathogenic	Retinitis pigmentosa 20	1998-03-17	no assertion criteria provided	literature only
Retina International	RCV000085169	SCV000117306	not provided	not provided		no assertion provided	not provided