CEP290 p.Asp321Glu

NM_025114.4(CEP290):c.963T>A (p.Asp321Glu) is a missense variant that replaces aspartic acid with glutamic acid at amino acid 321. This variant is present in gnomAD v4.1.1 at a total allele frequency of 0.00005764, with 87 alleles / 1,509,276 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0006 (PM2_Supporting). This variant has been reported in at least 1 proband with renal anomalies and renal disease who harbored the variant in the compound heterozygous state, however, the proband was not counted for PM3 because sufficient phenotype details were not reported and because the NM_025114.4(CEP290):c.5998A>G (p.Ile2000Val) variant suspected in trans has been classified as likely benign (PMID: 40718208). The variant has been reported in a second unpublished proband with retinal disease in the compound heterozygous state, however, the proband was not counted for PM3 because the NM_025114.4(CEP290):c.1092T>G (p.Ile364Met) variant confirmed in trans has been classified as likely benign (VCEP member-provided data). The computational predictor CADD gives a score of 24.9, which is above the ClinGen LCA/eoRD VCEP BP4 threshold of <17.3 and below the PP3 threshold of ≥25.3, so neither PP3 nor BP4 is met. The splicing impact predictor SpliceAI gives a delta score of 0.03 for acceptor loss, which is below the threshold of <0.1 and does not predict an impact on splicing. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for CEP290-related ciliopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting. (LCA/eoRD VCEP Specifications for CEP290 Version 1.0.0)