ClinVar

Description

Variant summary: CDH23 c.6083A>C (p.Asp2028Ala) results in a non-conservative amino acid change located in the classical calcium-binding motif (LDRE)-CA repeat domain (Zafar_2020) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245336 control chromosomes. c.6083A>C has been reported in the literature as a homozygous genotype in at-least four affected individuals with hearing loss (HL) from one consanguineous Pakistani family. The authors noted that the affected individuals of this family did not report any vision problems and appeared to have normal gait sophisticated function (evaluated through Romberg and Tandem gait tests). However, they do not rule out the possibility that night vision problems, retinal degeneration, or balance areflexia might develop as these children age (example, Zafar_2020 with authorship overlap in Richard_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.