ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.5237G>A (p.Arg1746Gln) (rs111033270)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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; 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 2018-09-18 criteria provided, single submitter clinical testing The R1746Q variant in the CDH23 gene has been reported previously in either the homozygous or compound heterozyous state in multiple unrelated individuals with an Usher syndrome phenotype (Bolz et al., 2001; Astuto et al., 2002; Schultz et al., 2011). The R1746Q variant is observed in 15/126682 (0.01%) alleles from individuals of European (Non-Finnish) background, and 18/277152 total alleles in large population cohorts (Lek et al., 2016). The R1746Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Functional studies indicate that R1746Q causes aberrant splicing through the creation of a novel cryptic splice acceptor site in exon 41 (Becirovic et al., 2008). We interpret R1746Q as a pathogenic variant.
Illumina Clinical Services Laboratory,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 Deafness, autosomal recessive 12; Usher syndrome type 1D; PITUITARY ADENOMA 5, MULTIPLE TYPES 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000254732 SCV000947772 pathogenic not provided 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1746 of the CDH23 protein (p.Arg1746Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs111033270, ExAC 0.01%). This variant has been observed to segregate with Usher syndrome and hearing loss in several families and it has been observed in an unrelated individual with Usher syndrome (PMID: 11138009, 25472526, 21940737). ClinVar contains an entry for this variant (Variation ID: 4916). Experimental studies have shown that this variant disrupts mRNA splicing resulting in in-frame deletion of 17 residues involving a Ca2+ binding motif (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
OMIM RCV000005198 SCV000025375 pathogenic Usher syndrome type 1D 2001-01-01 no assertion criteria provided literature only

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