CDH23 p.Glu956Lys

The p.Glu956Lys variant in CDH23 is a missense variant predicted to cause substitution of glutamic acid to lysine at amino acid 956. The highest population minor allele frequency in gnomAD v3.1.2 is 0.02895% (12/41444) in African/African American population which is greater than the PM2_Supporting thresholds defined by the ClinGen Hearing Loss Expert Panel (≤0.007%) and less than the BS1_supporting MAF of ≥0.0007 (0.07%) for autosomal recessive disorders (no codes met). The computational predictor REVEL produced a score of 0.616, which was just below the threshold to automatically apply PP3, but the Expert Panel decided to apply PP3 based upon manual review of alignments to examine homology. This variant has been detected in at least six probands with hearing loss without evidence of retinal disease (5 PM3_Very Strong points, PMID: 26763877,25963016, 22899989, Invitae Internal Data (SCV001228538.3)). Of those individuals, four harbored the p.Pro240Leu pathogenic variant in CDH23 with three individuals confirmed in trans (PMID 25963016, 22899989). The fifth individual harbored the p.Asp645Gly variant in CDH23, but phasing was not performed (PMID 25963016). The sixth proband carried a second pathogenic CDH23 variant in trans (Invitae Internal Data). 1 different missense variant, c.2867A>G (p.Glu956Gly) ClinVar Variation ID:1180655, in the same codon has been classified as likely pathogenic for AR sensorineural hearing loss by two submitters in ClinVar (PM5). In summary, this variant meets the criteria to be classified as pathogenic for AR hearing loss based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PP3, PM3_Very Strong, PM5. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023)