rs202052174

chr10-71803371-G-Achr10-71803371-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_022124.6(CDH23):c.7823G>A(p.Arg2608His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000686 in 1,600,450 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2608C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:14 B:2 O:1
• Conservation: PhyloP100: 7.78

Genes affected

CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_022124.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.1011363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.7823G>A	p.Arg2608His	missense_variant	55/70	ENST00000224721.12
CDH23	NM_001171933.1	c.1103G>A	p.Arg368His	missense_variant	8/23
CDH23	NM_001171934.1	c.1103G>A	p.Arg368His	missense_variant	8/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.7823G>A	p.Arg2608His	missense_variant	55/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 151976 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000677

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000667 AC: 150 AN: 224942 Hom.: 0 AF XY: 0.000631 AC XY: 77 AN XY: 122086

Gnomad AFR exome AF: 0.000232

Gnomad AMR exome AF: 0.000763

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000364

Gnomad FIN exome AF: 0.000541

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000356

GnomAD4 exome AF: 0.000698 AC: 1011 AN: 1448356 Hom.: 1 Cov.: 34 AF XY: 0.000673 AC XY: 484 AN XY: 719238

Gnomad4 AFR exome AF: 0.000243

Gnomad4 AMR exome AF: 0.000993

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000598

Gnomad4 FIN exome AF: 0.000516

Gnomad4 NFE exome AF: 0.000806

Gnomad4 OTH exome AF: 0.000501

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152094 Hom.: 0 Cov.: 31 AF XY: 0.000605 AC XY: 45 AN XY: 74324

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.000677

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000796 Hom.: 0

Bravo AF: 0.000820

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000953 AC: 8

ExAC AF: 0.000844 AC: 102

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:14 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:4 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 11, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2021	This variant is associated with the following publications: (PMID: 16963483, 21940737, 12786748, 28847902, 27018795, 12075507, 19683999, 21174530, 26969326, 30459346, 33576794) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Usher syndrome type 1D Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:2

Uncertain significance, criteria provided, single submitter	research	UAEU Genomics Laboratory, United Arab Emirates University	Dec 21, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 14, 2023

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. -

Neurodevelopmental abnormality Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Apr 03, 2020

- -

CDH23-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

Pituitary adenoma 5, multiple types Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 06, 2023

- -

Retinitis pigmentosa-deafness syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Rare genetic deafness Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 23, 2022

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. -

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.029	T;T;.;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
Sift4G	Uncertain	0.0020	D;.;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.66
MVP		0.74
MPC		0.45
ClinPred		0.14	T
GERP RS		4.5
Varity_R		0.54
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202052174; hg19: chr10-73563128; COSMIC: COSV99825106;