rs111033270

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_022124.6(CDH23):c.5237G>A(p.Arg1746Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00016 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1746W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 4.76

Variant links:

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]

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 10-71779316-G-A is Pathogenic according to our data. Variant chr10-71779316-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71779316-G-A is described in Lovd as [Pathogenic]. Variant chr10-71779316-G-A is described in Lovd as [Pathogenic]. Variant chr10-71779316-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.5237G>A	p.Arg1746Gln	missense_variant	41/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.5237G>A	p.Arg1746Gln	missense_variant	41/70	5	NM_022124.6	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000682

AC:

AN:

249208

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135214

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000161

AC:

236

AN:

1461678

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000192

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000145

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000171

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000240

AC:

ExAC

AF:

0.0000662

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	CDH23: PM3:Very Strong, PM2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 03, 2020	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. -

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 28, 2022

- -

CDH23-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 15, 2021

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._x000D_ _x000D_ 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. -

Usher syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 03, 2022

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. -

Pituitary adenoma 5, multiple types

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

Usher syndrome type 1

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Usher syndrome type 1D

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2001

- -

Childhood onset hearing loss

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

National Institute on Deafness and Communication Disorders, National Institutes of Health

Jul 08, 2021

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. -

Autosomal recessive nonsyndromic hearing loss 12

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

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 -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 02, 2016

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. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0017

T;T

Eigen

Benign

0.046

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.36

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.025

.;N

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

REVEL

Uncertain

0.35

Sift4G

Uncertain

0.012

D;.

Polyphen

0.62

.;P

Vest4

0.54

MVP

0.73

ClinPred

0.71

GERP RS

4.9

Varity_R

0.28

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.98

Position offset: 2

DS_AL_spliceai

0.42

Position offset: -49

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over