Submissions for variant NM_022124.6(CDH23):c.7823G>A (p.Arg2608His)

gnomAD frequency: 0.00059  dbSNP: rs202052174

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017329	SCV000062960	uncertain significance	Rare genetic deafness	2022-06-23	criteria provided, single submitter	clinical testing	The p.Arg2608His variant in CDH23 has been reported in 0.1% (7/6982) of chromosomes from probands with either hearing loss or Usher syndrome, at least one of whom had an alternate genetic cause for their disease (Astuto 2002, Jaijo 2010; Malm 2011, LMM data). However, this variant has also been identified in 0.1% (116/115288) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which suggests that the variant is unlikely to be causative for disease. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of p.Arg2608His is uncertain, these data suggest that it is more likely benign. ACMG/AMP criteria: BS1_Supporting, PP3.
Eurofins Ntd Llc (ga)	RCV000725220	SCV000335098	uncertain significance	not provided	2016-05-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000725220	SCV000577108	likely benign	not provided	2021-03-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16963483, 21940737, 12786748, 28847902, 27018795, 12075507, 19683999, 21174530, 26969326, 30459346, 33576794)
Illumina Laboratory Services, Illumina	RCV004528197	SCV000914467	uncertain significance	CDH23-related disorder	2017-04-28	criteria provided, single submitter	clinical testing	The CDH23 c.7823G>A (p.Arg2608His) missense variant has been reported in at least three studies in individuals with autosomal recessive nonsyndromic hearing loss, in which it is found in a total of 25 individuals, including in three in a compound heterozygous state and in 22 in a heterozygous state (Astuto et al. 2002; Wu et al. 2016). The p.Arg2608His variant is also reported in one study in a compound heterozygous state in an individual with Usher syndrome (Jaijo et al. 2010). The p.Arg2608His variant was absent from 256 controls, but is reported at a frequency of 0.00213 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg2608His variant is classified as a variant of unknown significance but suspicious for pathogenicity for CDH23-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics	RCV000988383	SCV001138082	uncertain significance	Retinitis pigmentosa-deafness syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000725220	SCV001413566	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001374881	SCV001572157	uncertain significance	Usher syndrome type 1D	2021-04-08	criteria provided, single submitter	research	The CDH23 c.7823G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3. Based on this evidence we have classified this variant as Variant of Uncertian Significance.
Genome-Nilou Lab	RCV001559300	SCV001781490	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001374881	SCV001781491	uncertain significance	Usher syndrome type 1D	2021-07-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725220	SCV002585226	likely pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725220	SCV003831494	uncertain significance	not provided	2022-08-11	criteria provided, single submitter	clinical testing
UAEU Genomics Laboratory, United Arab Emirates University	RCV001559300	SCV003926562	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2021-12-21	criteria provided, single submitter	research	The missense variant NM_022124.6(CDH23):c.7823G>A (p.Arg2608His) has been reported in compound heterozygous state in multiple publications in individuals affected with nonsyndromic deafness (PMID: 12075507, PubMed: 26969326, PMID: 27018795) Usher syndrome (PMID: 33576794, PMID: 19683999) in at least 4 individuals with a likely pathogenic or rare allele (PubMed: 33576794, PMID: 30459346, PMID: 12075507, PubMed: 26969326). This variant was also present in heterozygous state in individuals affected with non-syndromic sensorineural hearing loss (PMID: 30459346, PMID: 27018795). Another variant causing a different amino acid change (p.Arg2608Cys)) has been reported in an individual with nonsyndromic recessive deafness, who also had another variant in the same gene in homozygous state (PubMeD: 26226137). The p.Arg2608His variant is observed in 107/99,932 (0.1071%) alleles from individuals of gnomAD Non Finnish European background in gnomAD database, which is higher than that specified by the hearing loss expert working group (PubMed: 30311386). Computational prediction tools and conservation analysis indicate that this change could be deleterious. Structural modeling studies indicated that this variant affect one of the outward facing residues in the CDH23 extracellular domain and might affect intramolecular hydrogen bonding and cis- dimer formation (PMID: 30033219). In summary, though the variant has been reported frequently patients with disease, the available evidence is insufficient to classify this variant with certainty. For these reasons, this variant has been classified as Uncertain significance.
Baylor Genetics	RCV003473285	SCV004210658	uncertain significance	Pituitary adenoma 5, multiple types	2023-07-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039276	SCV004241502	uncertain significance	not specified	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.7823G>A (p.Arg2608His) results in a non-conservative amino acid change located in the cadherin repeat region (IPR002126) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 1,593,492 control chromosomes in the gnomAD database (v4.0 dataset), including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in CDH23 causing Usher Syndrome (0.0032), allowing no conclusion about variant significance. c.7823G>A has been reported in the literature in compound heterozygous state together with a second pathogenic variant (though in most of these cases the phase was not specified) in individuals affected with Usher Syndrome (e.g. Jaijo_2009, Colombo_2021), nonsyndromic hearing loss (Astuto_2002, Wu_2016), and retinal disease (Zampaglione_2022). On the other hand, the variant has been reported in homozygous state in a patient affected with retinal disease (without hearing loss), who carried a homozygous pathogenic variant in another gene, which could explain the phenotype (Ortube_2014). The variant has been also reported in (apparent) heterozygosity in affected individuals in whom a second (likely) pathogenic mutation was not identified (e.g. Fuster-Garcia_2018, Mansard_2021, Wu_2016, Sloan-Heggen_2016), however, in one of these cases co-occurring pathogenic variants could explain the phenotype (Mansard_2021). In many of the reported cases, the CDH23 gene was not completely sequenced, or other genes and large rearrangements were not assessed, thus these reports do not provide conclusive evidence for causality. 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: 12075507, 27018795, 26969326, 19683999, 30459346, 33576794, 34948090, 24444108, 36460718, 34906470). 13 submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 and classified the variant with conflicting assessments, i.e. as likely pathogenic (n=2), VUS (n=9), or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001264702	SCV001442885	uncertain significance	Neurodevelopmental abnormality	2020-04-03	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000725220	SCV001958480	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725220	SCV001970142	uncertain significance	not provided		no assertion criteria provided	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000725220	SCV002011389	likely pathogenic	not provided	2021-11-03	flagged submission	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483451	SCV004228656	not provided	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 01-06-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.