Submissions for variant NM_022124.6(CDH23):c.4762C>T (p.Arg1588Trp)

dbSNP: rs137937502

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001103916	SCV001260729	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241939	SCV001414995	likely pathogenic	not provided	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1588 of the CDH23 protein (p.Arg1588Trp). This variant is present in population databases (rs137937502, gnomAD 0.1%). This missense change has been observed in individuals with CDH23-related conditions (PMID: 23967202, 25587757, 26346818, 27792758, 30123251, 30828794, 31872526, 34416374, 34824372, 35020051). ClinVar contains an entry for this variant (Variation ID: 877825). Invitae Evidence 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 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. 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.
3billion, Medical Genetics	RCV001103916	SCV002059032	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2022-01-03	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000180, PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV001241939	SCV003831039	uncertain significance	not provided	2021-11-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001241939	SCV004023458	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing	Reported in the homozygous state in patients with hearing loss as well as a relative with normal hearing (Miyagawa et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34416374, 31872526, 23967202, 30828794, 28265457, 26346818, 25587757, 26763877, 17850630, 27792758, 24767429, 30123251, 34426522, 34403091, 33297549, 34599366, 34824372, 35020051, 36468022, 22899989)
Baylor Genetics	RCV003473716	SCV004210586	likely pathogenic	Pituitary adenoma 5, multiple types	2024-03-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782651	SCV005395813	likely pathogenic	Usher syndrome	2024-09-17	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.4762C>T (p.Arg1588Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 1610756 control chromosomes in the gnomAD database, including 2 homozygotes, and predominantly at a frequency of 0.0036 within the East Asian subpopulation. The observed variant frequency within East Asian control individuals in the gnomAD database is 1.12x the estimated maximal expected allele frequency for a pathogenic variant in CDH23 causing a disease phenotype (0.0032), and we note that non-syndromic deafness may not be severe enough to exclude individuals from the gnomAD dataset (e.g. GJB2 c.35del). However, c.4762C>T has been reported in the literature in numerous homozygous and compound heterozygous individuals affected with autosomal recessive non-syndromic deafness, including cases where it has been confirmed to be in trans with a pathogenic variant, although at least one homozygous unaffected individual has also been reported which may suggest decreased penetrance or a hypomorphic allele (e.g. Miyagawa_2012, Kim_2016, Hu_2018, Usami_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30123251, 27792758, 22899989, 35020051). ClinVar contains an entry for this variant (Variation ID: 877825). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005047309	SCV005675033	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2024-01-23	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV005047309	SCV005880032	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types		criteria provided, single submitter	clinical testing	PM3_VeryStrong