Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000710339 | SCV000840533 | likely pathogenic | Usher syndrome | 2023-06-27 | reviewed by expert panel | curation | The c.380A>G (NM_022124.6(CDH23):c.380A>G (p.Asp127Gly)) variant in CDH23 is a missense variant predicted to cause substitution of aspartate by glycine at amino acid 127. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.796 which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in one individual with autosomal recessive Usher syndrome. For this individual, they were compound heterozygous for the variant and a pathogenic variant (NM_022124.6(CDH23):c.1949dup (p.Leu651fs) (SCV000271345.2) ) and this individual was confirmed in trans by family testing (1.0 point, PM3; LMM internal data). The patient with the variant had congenital severe-profound hearing loss with vestibular complications and ophthalmology-related issues, features highly specific to Usher syndrome (LMM Internal Data; PP4). This variant was re-reviewed on 1.18.2023 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP. In summary, this variant is classified as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_supporting, PP3, PM3, PP4 (ClinGen Hearing Loss VCEP Specifications Version 2; 6/27/2022). |
| Laboratory for Molecular Medicine, |
RCV000213965 | SCV000271558 | likely pathogenic | Rare genetic deafness | 2016-05-23 | criteria provided, single submitter | clinical testing | The p.Asp127Gly variant in CDH23 has been identified by our laboratory highly li kely in trans with a pathogenic variant in CDH23 in an individual with clinical features of Usher syndrome (this individual's family). It has not been identifie d in large population studies. Computational prediction tools and conservation a nalysis suggest that this variant may impact the protein, though this informatio n is not predictive enough to determine pathogenicity. The presence of this vari ant in trans with a pathogenic variant in an individual with Usher syndrome incr eases the likelihood that the p.Asp127Gly variant is pathogenic. In summary, alt hough additional studies are required to fully establish its clinical significan ce, this variant is likely pathogenic. |
| King Laboratory, |
RCV003155129 | SCV003844196 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 12 | 2023-02-28 | criteria provided, single submitter | research | This variant occurred in compound heterozygosity with a CDH23 missense variant in two siblings with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). At the time of recruitment, neither sibling had any known visual impairment (ages 13y and 9y). This patient's family has no other history of hearing loss. This variant is a missense at a completely conserved site in a cadherin domain of the CDH23 protein and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported previously in an individual with hearing loss and is currently classified as likely pathogenic on ClinVar and is not found on gnomAD. Based on co-segregation with the phenotype in the family, consistently predicted functional effect, previous classification as likely pathogenic, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. |
| Baylor Genetics | RCV003474999 | SCV004212282 | likely pathogenic | Pituitary adenoma 5, multiple types | 2023-06-13 | criteria provided, single submitter | clinical testing |