Submissions for variant NM_000329.3(RPE65):c.1244C>T (p.Ala415Val)

gnomAD frequency: 0.00001  dbSNP: rs1064795255

Total submissions: 2

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	RCV003766693	SCV004697382	likely pathogenic	RPE65-related recessive retinopathy	2024-02-18	reviewed by expert panel	curation	NM_000329.3(RPE65):c.1244C>T is a missense variant causing substitution of alanine with valine at position 415. This variant is present in gnomAD v.2.1.1 at an allele frequency of 0.0001638, with 1 allele / 6104 total alleles in the Remaining individuals population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.886dup (p.Arg296fs) variant suspected in trans (PMID: 27102010, PMID: 30268864, PMID: 37660736), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (0.5 total points, PM3_Supporting). At least one proband harboring this variant has exhibited a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), onset before age 5 years (1 pt), flat ERG responses for rods (0.5 pts) and cones (1 pt), and improvement of night vision following RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (11 total pts, PMID: 37660736, PP4_Moderate). The computational predictor REVEL gives a score of 0.775, which is above the ClinGen LCA / eoRD VCEP threshold of >=0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). 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, PM3_Supporting, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
GeneDx	RCV000483168	SCV000570884	likely pathogenic	not provided	2018-01-05	criteria provided, single submitter	clinical testing	The A415V variant in the RPE65 gene has been reported previously as a pathogenic variant, in trans with another RPE65 variant, in a child with Leber congenital amaurosis (Weleber et al., 2016). The A415V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A415V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The A415V variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.