Submissions for variant NM_022124.6(CDH23):c.2524C>T (p.Arg842Trp)

gnomAD frequency: 0.00003  dbSNP: rs368496658

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000318745	SCV000363650	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV004529503	SCV000363651	uncertain significance	CDH23-related disorder	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000278654	SCV000363652	uncertain significance	Usher syndrome type 1D	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000766847	SCV000571529	uncertain significance	not provided	2016-09-08	criteria provided, single submitter	clinical testing	The R842W variant in the CDH23 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R842W 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 predicts this variant is probably damaging to the protein structure/function. We interpret R842W as a variant of uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000487080	SCV000712302	uncertain significance	not specified	2020-06-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg842Trp variant has been previously reported by our laboratory in 2 individual with sensorineural hearing loss, 1 had a likely pathogenic CDH23 variant confirmed in trans, and 1 had a second variant of uncertain significance in CDH23, though cis/trans was not determined. This variant has been reported in 0.005% (7/128322) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), and it has also been reported in ClinVar (Variation ID 300415). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3, PP3.
Pars Genome Lab	RCV000278654	SCV001736840	uncertain significance	Usher syndrome type 1D	2021-05-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002480095	SCV002776941	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2021-07-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766847	SCV003281270	uncertain significance	not provided	2023-12-11	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 842 of the CDH23 protein (p.Arg842Trp). This variant is present in population databases (rs368496658, gnomAD 0.006%). 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: 300415). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000487080	SCV004803925	uncertain significance	not specified	2024-01-20	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.2524C>T (p.Arg842Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249148 control chromosomes, predominantly at a frequency of 5.3e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2524C>T in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 300415). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001271853	SCV001453325	uncertain significance	Usher syndrome type 1	2020-09-16	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001824727	SCV002075208	not provided	Usher syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 03-17-2020 by Lab or GTR ID 21766. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.