Submissions for variant NM_022124.6(CDH23):c.1853A>G (p.Tyr618Cys)

dbSNP: rs778493031

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521699	SCV000620245	uncertain significance	not provided	2017-09-06	criteria provided, single submitter	clinical testing	The Y618C variant in the CDH23 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Y618C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Y618C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret Y618C as a variant of uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825300	SCV000966595	uncertain significance	not specified	2019-01-04	criteria provided, single submitter	clinical testing	The c.Tyr618Cys variant in CDH23 has been reported by our laboratory in 1 indivi dual with progressive severe hearing loss as an assumed de novo variant. This in dividual also harbored a second variant of uncertain significance in CDH23. This variant was identified in 1/104828 European chromosomes by gnomAD (http://gnoma d.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signific ance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM6.
CeGaT Center for Human Genetics Tuebingen	RCV000521699	SCV001246546	uncertain significance	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Invitae	RCV000521699	SCV002168242	uncertain significance	not provided	2023-08-17	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 451527). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. This variant has not been reported in the literature in individuals affected with CDH23-related conditions. This variant is present in population databases (rs778493031, gnomAD 0.001%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 618 of the CDH23 protein (p.Tyr618Cys).