ClinVar Genomic variation as it relates to human health

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 (less than or equal to 0.007%) and less than the BS1_supporting MAF of greater than or equal to 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)

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 956 of the CDH23 protein (p.Glu956Lys). This variant is present in population databases (rs756147087, gnomAD 0.03%). This missense change has been observed in individual(s) with deafness (PMID: 22899989, 25963016; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 444219). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CDH23 protein function. For these reasons, this variant has been classified as Pathogenic.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28714951, 26763877, 31785789, 26346818, 35020051, 22899989, 25963016, 30303587)