Submissions for variant NM_000329.3(RPE65):c.257C>A (p.Thr86Asn)

dbSNP: rs1645931073

Total submissions: 3

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	RCV003770791	SCV004697388	uncertain significance	RPE65-related recessive retinopathy	2024-02-19	reviewed by expert panel	curation	NM_000329.3(RPE65):c.257C>A is a missense variant causing substitution of threonine with asparagine at position 86. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 affected proband who harbored the variant in the homozygous state due to consanguinity (parents first cousins, VCEP member-provided data). However, the proband was not counted for PM3 because sufficient phenotype details were unavailable. The computational predictor REVEL gives a score of 0.637, which is below the ClinGen LCA / eoRD VCEP threshold of >=0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.06 for acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of >=0.2 and does not strongly predict an impact on splicing. Another missense variant in the same codon, NM_000329.3(RPE65):c.257C>T (p.Thr86Ile), has been classified as a variant of uncertain significance for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP, so PM5 is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001326816	SCV001517866	uncertain significance	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with asparagine at codon 86 of the RPE65 protein (p.Thr86Asn). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RPE65-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	RCV001760420	SCV001991938	uncertain significance	not provided	2019-04-23	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge