Submissions for variant NM_022124.6(CDH23):c.6083A>C (p.Asp2028Ala)

dbSNP: rs762226905

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001869030	SCV002140511	pathogenic	not provided	2023-09-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 2028 of the CDH23 protein (p.Asp2028Ala). This variant is present in population databases (rs762226905, gnomAD 0.003%). This missense change has been observed in individual(s) with deafness (PMID: 30303587, 32842620). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 619171). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265874	SCV002547550	likely pathogenic	Usher syndrome	2022-05-11	criteria provided, single submitter	clinical testing	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.
Laboratory of NeuroGenetics and Regenerative Medicine, University of Maryland School of Medicine	RCV000761609	SCV000886628	pathogenic	Autosomal recessive nonsyndromic hearing loss 12	2018-07-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291216	SCV001479641	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research