Submissions for variant NM_022124.6(CDH23):c.790G>T (p.Asp264Tyr)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003557510	SCV004294742	likely pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 264 of the CDH23 protein (p.Asp264Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Usher syndrome (PMID: 21436283). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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. This variant disrupts the p.Asp264 amino acid residue in CDH23. Other variant(s) that disrupt this residue have been observed in individuals with CDH23-related conditions (PMID: 31322239), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.