Submissions for variant NM_022124.6(CDH23):c.5237G>A (p.Arg1746Gln)

gnomAD frequency: 0.00016  dbSNP: rs111033270

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844622	SCV000062889	pathogenic	Rare genetic deafness	2016-08-02	criteria provided, single submitter	clinical testing	The p.Arg1746Gln variant in CDH23 has been reported in >10 probands with Usher s yndrome and in 3 individuals with hearing loss (Bolz 2001, Astuto 2002, Schultz 2011, Bujakowska 2014, LMM data). Eight of these probands were compound heterozy gous for a second pathogenic variant, and two were homozygous. The variant has also segregated in 11 affected family members across 3 families (Bolz 2001, Schu ltz 2011, LMM data). This variant has been identified in 15/126682 European ch romosomes by the Genome Aggregation Database (gnomAd, http://gnomad.broadinstitu te.org; dbSNP rs111033270); however, its frequency is low enough to be consisten t with a recessive carrier frequency. In addition, mRNA studies revealed that t his variant affects splicing, causing in-frame skipping of 51 base pairs and sub sequently leading to a loss of 17 amino acids of the protein (Becirovic 2008). I n summary, this variant meets criteria to be classified as pathogenic for autoso mal recessive Usher syndrome based on case observations, segregation studies, an d functional evidence. ACMG/AMP Criteria applied: PM3_Very Strong, PP1_Strong, PM2, PS3_Moderate.
GeneDx	RCV000254732	SCV000321509	pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect; minigene functional splicing assay showed p.(R1746Q) causes aberrant splicing: a novel acceptor site is generated and exclusively used, resulting in in-frame exclusion of 51 bp, a predicted loss of 17 amino acid residues, including a DINDN Ca2+-binding motif, in EC17 (Becirovic et al., 2008); This variant is associated with the following publications: (PMID: 25468891, 28847902, 33089500, 12075507, 20613545, 25472526, 21940737, 32795431, 31980526, 32707200, 32037395, 35020051, 32991204, 11138009, 35186827, 18273900, 35076463, 35440622, 36056583)
Illumina Laboratory Services, Illumina	RCV000405146	SCV000363783	pathogenic	CDH23-Related Disorders	2017-04-27	criteria provided, single submitter	clinical testing	The CDH23 c.5237G>A (p.Arg1746Gln) missense variant has been identified in individuals with both Usher syndrome and nonsyndromic hearing loss who present with a range of phenotypes. The majority of the patients reported in the literature were diagnosed with Usher syndrome but some individuals with nonsyndromic hearing loss were also identified. Across a selection of the literature, the p.Arg1746Gln variant was reported in a homozygous state in six patients, in a compound heterozygous state in eight patients, in a heterozygous state in two patients in whom a second variant was not identified, and in a heterozygous state in one unaffected individual (Bolz et al. 2001; Astuto et al. 2002; Schultz et al. 2011; Zhao et al. 2015). Control data are not available for this variant, which is reported at a frequency of 0.00011 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional testing by Becirovic et al. (2008) indicated that the p.Arg1746Gln variant creates a novel splice acceptor site that results in an in-frame deletion of 51 base pairs and the exclusion of a calcium binding motif. Based on the collective evidence, the p.Arg1746Gln variant is classified as pathogenic for CDH23-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics, Fulgent Genetics	RCV000763215	SCV000893841	pathogenic	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2022-04-28	criteria provided, single submitter	clinical testing
Invitae	RCV000254732	SCV000947772	pathogenic	not provided	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1746 of the CDH23 protein (p.Arg1746Gln). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 17 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs111033270, gnomAD 0.01%). This missense change has been observed in individuals with Usher syndrome and autosomal recessive deafness (PMID: 11138009, 21940737, 25472526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4916). 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 with a negative predictive value of 95%. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 41 (PMID: 18273900, 21940737). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001073594	SCV001239145	pathogenic	Retinal dystrophy	2019-07-09	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000254732	SCV001475760	pathogenic	not provided	2020-09-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported to associate with Usher syndrome and nonsyndromic hearing loss (PMID: 11138009, 12075507, 21940737). Assessment of experimental evidence suggests this variant results in abnormal RNA splicing. Experiments show this variant creates a novel splice site, resulting in the in-frame deletion of 17 amino acids from the protein (PMID: 18273900). This variant segregates with disease in at least one family. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
National Institute on Deafness and Communication Disorders, National Institutes of Health	RCV001328020	SCV001519353	pathogenic	Childhood onset hearing loss	2021-07-08	criteria provided, single submitter	research	PS1, PS3_moderate, PM2, PM3_very strong, PP3 (non REVEL) / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging.
Revvity Omics, Revvity	RCV000254732	SCV002016987	pathogenic	not provided	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222340	SCV002500832	pathogenic	Usher syndrome	2022-03-03	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.5237G>A (p.Arg1746Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic exonic alternate 3' splice acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in the exclusion of 51-base pairs of exonic sequence consistent with the computational predictions (example, Becirovic_2008). The variant allele was found at a frequency of 6.8e-05 in 249208 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CDH23 causing Usher Syndrome (6.8e-05 vs 0.0032), allowing no conclusion about variant significance. c.5237G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with hearing loss and/or Usher syndrome (example, Bolz_2001, Kannan-Sundhari_2020, Schultz_2011). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272010	SCV002557461	pathogenic	Autosomal recessive nonsyndromic hearing loss 12	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness 12 (MIM#601386) and Usher syndrome, type 1D/F (MIM#601067). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice variant (non-canonical) proven to affect splicing of the transcript with uncertain effect on protein structure. Variant is predicted to result in a missense amino acid change from arginine to glutamine. Exon-trapping assay demonstrated aberrant splicing, predicting an in-frame deletion of 17 amino acids p.(Val1730_Arg1746del) (PMID: 18273900). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (72 heterozygotes, 0 homozygotes). (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in greater than ten patients with Usher syndrome or non-syndromic hearing loss (Clinvar, PMID: 11138009, 12075507, 20613545, 21940737, 25468891, 35186827). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002512799	SCV003721963	pathogenic	Inborn genetic diseases	2021-01-15	criteria provided, single submitter	clinical testing	The c.5237G>A (p.R1746Q) alteration is located in exon 41 (coding exon 40) of the CDH23 gene. This alteration results from a G to A substitution at nucleotide position 5237, causing the arginine (R) at amino acid position 1746 to be replaced by a glutamine (Q). Based on data from the Genome Aggregation Database (gnomAD), the CDH23 c.5237G>A alteration was observed in 0.0071% (20/280,608) total alleles studied, with a frequency of 0.013% (17/128,412) in the European (Non-Finnish) subpopulation. The c.5237G>A (p.R1746Q) alteration has been previously reported in either the homozygous or compound heterozygous state in multiple unrelated individuals with an Usher syndrome or deafness phenotype (Bolz, 2001; Schultz, 2011; Zhao, 2015) The p.R1746 amino acid is conserved in available vertebrate species. Functional analysis demonstrated that the p.R1746Q alteration creates a new cryptic splice acceptor site (Becirovic, 2008) The in silico prediction for the p.R1746Q alteration is inconclusive. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000254732	SCV003916606	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	CDH23: PM3:Very Strong, PM2, PP3, PS3:Supporting
Baylor Genetics	RCV003472972	SCV004210579	pathogenic	Pituitary adenoma 5, multiple types	2023-10-30	criteria provided, single submitter	clinical testing
OMIM	RCV000005198	SCV000025375	pathogenic	Usher syndrome type 1D	2001-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001274889	SCV001459442	pathogenic	Usher syndrome type 1	2020-09-16	no assertion criteria provided	clinical testing