Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003239292 | SCV003936866 | pathogenic | Nonsyndromic genetic hearing loss | 2023-06-26 | reviewed by expert panel | curation | The c.6085C>T variant in CDH23 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 2029 (p.Arg2029Trp). The highest population minor allele frequency in gnomAD v2.1.1 is 0.02% (3/17816 alleles) in the East Asian population. (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in many individuals with hearing loss or deafness, without any reported vision loss or evidence of retinopathy. Of those individuals, over 10 were homozygous or compound heterozygous for the variant and a pathogenic or likely pathogenic and many of those were confirmed in trans (6.75 PM3_Very Strong points, PMID: 35020051, 25963016, 22899989, 17850630). The variant has been reported to segregate with hearing loss in 1 affected family member from 1 family (PP1_Supporting; PMID: 22899989, 17850630). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VeryStrong, PP3, PP1. (VCEP specifications version 2; 06.26.2023). |
| Division of Hearing and Balance Research, |
RCV000515743 | SCV000611804 | pathogenic | Autosomal recessive nonsyndromic hearing loss 12 | 2017-07-01 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV002251483 | SCV002522121 | likely pathogenic | not provided | 2022-05-17 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25587757, 26763877, 32027099, 34599366, 35020051, 17850630, 22899989, 25963016) |
| Baylor Genetics | RCV003476213 | SCV004210606 | likely pathogenic | Pituitary adenoma 5, multiple types | 2023-10-03 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002251483 | SCV004294747 | pathogenic | not provided | 2024-01-03 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2029 of the CDH23 protein (p.Arg2029Trp). This variant is present in population databases (rs750880909, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness (PMID: 17850630, 22899989, 25963016). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 446446). 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. |