Submissions for variant NM_000329.3(RPE65):c.302C>T (p.Thr101Ile)

gnomAD frequency: 0.00001  dbSNP: rs1444234037

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	RCV004801929	SCV005423708	likely pathogenic	RPE65-related recessive retinopathy	2024-12-12	reviewed by expert panel	curation	The NM_000329.3(RPE65):c.302C>T (p.Thr101Ile) variant is a missense variant in RPE65 causing a substitution of threonine with isoleucine at position 101. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 8.474e-7, with 1 / 1180026 alleles in the European (Non-Finnish) 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 0.88, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 1.27% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 19431183). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.271C>T p.Arg91Trp variant confirmed in trans by next-generation sequencing data (1 point, VCEP member-provided data), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PM3). 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, PS3_Supporting, PM3 (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Blueprint Genetics	RCV001073555	SCV001239104	likely pathogenic	Retinal dystrophy	2019-06-15	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV001089888	SCV001245395	likely pathogenic	Leber congenital amaurosis 2	2020-02-14	criteria provided, single submitter	curation	This variant is interpreted as likely pathogenic for Leber congenital amaurosis 2, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PS3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002554669	SCV003523286	uncertain significance	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2022-11-28	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects RPE65 function (PMID: 19431183). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 101 of the RPE65 protein (p.Thr101Ile). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy (PMID: 17964524; Invitae). ClinVar contains an entry for this variant (Variation ID: 865946). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.