ClinVar Genomic variation as it relates to human health

NM_000329.3(RPE65):c.434C>A is a missense variant that causes substitution of alanine with aspartic acid at position 145. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of fundus albipunctatus (2 pts) with genotyping by exome sequencing without finding an alternative explanation for disease (2 pts), nyctalopia (0.5 pts), onset at age 3.3 years (1 pt), undetectable dark-adapted electroretinogram (0.5 pts), and severely reduced light-adapted electroretinogram (1 pt), which together are specific for RPE65-related recessive retinopathy (7 total pts, PMID: 31273949, PP4). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.200T>G (p.Leu67Arg) or the NM_000329.3(RPE65):c.1399C>G (p.Pro467Ala) variants confirmed in trans, which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 points, PMID: 23661369, PMID: 31273949, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 31273949, PP1). Two other missense variants in the same codon, NM_000329.3(RPE65):c.433G>A (p.Ala145Thr) (PMID: 26906952) and NM_000329.3(RPE65):c.433G>C (p.Ala145Pro) (PMID: 28224992) have been classified for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP, however, the PM5 code has not been considered in order to avoid circularity. The computational predictor REVEL gives a score of 0.929, 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_Strong, PP1, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).