Submissions for variant NM_022124.6(CDH23):c.6533T>A (p.Ile2178Asn)

gnomAD frequency: 0.00001  dbSNP: rs772953914

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001971638	SCV002264045	uncertain significance	not provided	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 2178 of the CDH23 protein (p.Ile2178Asn). This variant is present in population databases (rs772953914, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 1477521). 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. 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.
King Laboratory, University of Washington	RCV003155452	SCV003844125	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 highly 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 a variant of unknown significance on ClinVar, and it is found in 4 heterozygous individuals on gnomAD. Based on co-segregation with the phenotype in the family, consistently predicted functional effect, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.