ClinVar Genomic variation as it relates to human health

The allele frequency of the c.719C>T (p.Pro240Leu) variant in the CDH23 gene is 0.05% (10/17246) of East Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been reported in > 10 probands with hearing loss without evidence of retinal disease, including >5 homozygotes, at least 1 compound heterozygote with c.6712+1G>A variant, and >5 compound heterozygotes with rare variants of uncertain significance (PM3_Strong; PMID:24164807, 24618850, 25963016, 26264712, 17850630, 22899989). This variant has also segregated in 3 siblings with hearing loss (PP1_Strong, PMID: 17850630, 22899989). The variant was identified in the heterozygous state in a patient with Usher syndrome who also harbored a homozygous missense variant in MYO7A (PMID: 24618850). A case-control meta analysis found that the p.Pro240Leu variant was associated with a 12-fold higher risk of hearing loss compared to the wild-type allele (OR = 11.68; 95% CI = 3.16–43.24; PS4), though it should be noted that it appears that some probands were included in more than one study included in the meta-analysis (PMID 30367262). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_Strong, PM3_Strong, PM2_Supporting, PS4.

Across a selection of the available literature, the CDH23 c.719C>T (p.Pro240Leu) missense variant has been identified in a homozygous state in nine affected individuals, in a compound heterozygous state in 20 affected individuals, and in a heterozygous state in 21 affected individuals. The phenotypic spectrum of these patients varied from mild to profound hearing loss, with age of onset ranging from infant to adult onset, with the majority presenting with bilateral hearing loss (Wagatsuma et al. 2007; Miyagawa et al. 2012; Miyagawa et al. 2013; Kim et al. 2015). One patient who was heterozygous for the p.Pro240Leu variant, was diagnosed with Usher syndrome. This individual also carried a homozygous missense variant in the MYO7A gene (Yoshimura et al. 2014). Of the 21 affected heterozygotes with hearing loss, 19 were reported in a study where the second allele may not have been ascertained due to limitations of a genotyping assay; five were from families with at least two affected generations but segregation of the variant was not demonstrated by the authors (Miyagawa et al. 2012). Variants in CDH23 have not been historically reported in association with dominant hearing loss, however a dominant presentation cannot be ruled out in these families. The p.Pro240Leu variant was reported in two of 676 controls in a heterozygous state and is reported at a frequency of 0.001276 in the East Asian population of the Exome Aggregation Consortium database. Based on the collective evidence, the p.Pro240Leu variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 30367262, PS4_S) and co-segregated with Deafness, autosomal recessive 12 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 17850630, 22899989, PP1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 24164807, 24618850, 25963016, 26264712, 17850630, 22899989, PM3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000040, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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: 26763877, 24164807, 30367262, 25963016, 27792758, 24767429, 26264712, 17850630, 23967202, 24618850, 22899989)

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 240 of the CDH23 protein (p.Pro240Leu). This variant is present in population databases (rs121908354, gnomAD 0.06%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 17850630, 22443853, 22899989, 23967202, 24767429, 25279224, 25963016, 26264712, 26763877, 27583405, 27792758). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4928). 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) performed at Invitae indicates that this missense variant is not expected to disrupt CDH23 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.