Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001870388 | SCV002123330 | pathogenic | not provided | 2023-01-21 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1357019). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. This variant is present in population databases (rs764949139, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Leu382Thrfs*54) in the CDH23 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH23 are known to be pathogenic (PMID: 11138009, 21940737). |
| Fulgent Genetics, |
RCV002503392 | SCV002809684 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types | 2021-07-09 | criteria provided, single submitter | clinical testing | |
| Clinical Genomics Program, |
RCV003447325 | SCV004174270 | pathogenic | Usher syndrome type 1D | 2021-04-14 | no assertion criteria provided | clinical testing | The p.Leu382Thrfs*54 variant in the CDH23 gene has not been previously reported in association with disease. This variant was identified with the p.Trp2811* variant in this individual; however, their phase is currently unknown. The p.Leu382Thrfs*54 variant has been identified in 1/112608 Non-Finnish European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Leu382Thrfs*54 variant results in a 33bp deletion, which causes a shift in the protein reading frame, leading to a premature termination codon 54 amino acids downstream. Loss of function is an established mechanism of disease for the CDH23 gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Leu382Thrfs*54 variant as pathogenic for Usher syndrome type ID in an autosomal recessive manner based on the information above. [ACMG evidence codes used: PVS1; PM3_supporting; PM2] |