rs111033271

Variant names:

Variant summary

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

The NM_022124.6(CDH23):c.6442G>A(p.Asp2148Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000898 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 9.91

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

MetaRNN computational evidence supports a deleterious effect, 0.847

PP5

Variant 10-71793370-G-A is Pathogenic according to our data. Variant chr10-71793370-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71793370-G-A is described in Lovd as [Likely_pathogenic]. Variant chr10-71793370-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.6442G>A	p.Asp2148Asn	missense_variant	Exon 48 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.6442G>A	p.Asp2148Asn	missense_variant	Exon 48 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000923

AC:

AN:

249170

Hom.:

AF XY:

0.0000814

AC XY:

AN XY:

135216

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

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:

0.000195

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000896

AC:

131

AN:

1461682

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000113

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000103

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000238

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000909

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDH23: PM3:Very Strong, PP1:Strong, PM2 -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2148 of the CDH23 protein (p.Asp2148Asn). This variant is present in population databases (rs111033271, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive deafness and/or Usher syndrome (PMID: 12075507, 12522556, 21940737, 27460420). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4922). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CDH23 protein function. For these reasons, this variant has been classified as Pathogenic. -

Oct 24, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified with a second variant in additional patients with CDH23-related disorders in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 28000701, 27460420); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12522556, 22652773, 33724713, 30531642, 21940737, 31816670, 15353998, 12075507, 27460420, 28000701, BuianovaA2024[Preprint]) -

Feb 08, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 12

Pathogenic:2

Feb 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 03, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDH23 c.6442G>A (p.Asp2148Asn) missense variant has been reported in three studies in which it is found in a total of eight individuals with hearing loss, including in two in a homozygous state, in five in a compound heterozygous state, and in one where zygosity was not specified (Astuto et al. 2002; De Brouwer et al. 2003; Schultz et al. 2011). This variant was also identified in 14 unaffected individuals in a heterozygous state. The p.Asp2148Asn variant was absent from a total of 296 controls and is reported at a frequency of 0.00015 in the European (non-Finnish) population of Exome Aggregation Consortium. Protein modelling studies revealed the Asp2148 residue is conserved and located in a calcium binding domain. Other aspartic acid to asparagine substitions associated with disease have been reported in these domains (de Brouwer et al. 2003). Based on the evidence, the p.Asp2148Asn variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Pathogenic:1

Apr 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDH23-related disorder

Pathogenic:1

Jun 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDH23 c.6442G>A variant is predicted to result in the amino acid substitution p.Asp2148Asn. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with non-syndromic autosomal recessive deafness and Usher syndrome (Astuto et al. 2002. PubMed ID: 12075507; De Brouwer et al. 2003. PubMed ID: 12522556; Schultz et al. 2011. PubMed ID: 21940737; Bonnet et al. 2016. PubMed ID: 27460420; Li et al. 2021. PubMed ID: 33724713). Of note, this variant has been reported to segregate with disease in at least two families (De Brouwer et al. 2003. PubMed ID: 12522556; Schultz et al. 2011. PubMed ID: 21940737). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Usher syndrome

Pathogenic:1

Jan 22, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDH23 c.6442G>A (p.Asp2148Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 249170 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (9.2e-05 vs 0.0032), allowing no conclusion about variant significance. c.6442G>A has been reported in the literature in multiple individuals affected with Usher Syndrome and Nonsyndromic hearing loss (e.g. Astuto_2002, deBrouwer_2003, Schultz_2011, Bonnet_2016) and also observed to segregate with disease. These data indicate that the variant is very likely to be associated with disease. 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, 27460420, 21940737, 12522556). ClinVar contains an entry for this variant (Variation ID: 4922). Based on the evidence outlined above, the variant was classified as pathogenic. -

Pituitary adenoma 5, multiple types

Pathogenic:1

Mar 12, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 12;C1848634:Usher syndrome type 2A

Pathogenic:1

Oct 05, 2016

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1D

Pathogenic:1

Feb 09, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (G>A) at position 6442 of the coding sequence of the CDH23 gene that results in an aspartic acid to asparagine amino acid change at residue 2148 of the cadherin related 23 protein. This residue falls in the extracellular cadherin 20 domain of the protein (UniProt). This is a previously reported variant (ClinVar 4922) that has been observed in homozygous and compound heterozygous state in several individuals and families affected by hearing loss and/or Usher syndrome (PMID: 12522556, 28000701, 33724713, 12075507, 21940737, 27460420). This variant is present in 1454 of 1613806 alleles (0.008985%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Asp2148 residue at this position is highly conserved across the vertebrate species examined. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PM3, PP1, PP3, PS4 -

Usher syndrome type 1

Pathogenic:1

Aug 19, 2021

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Rare genetic deafness

Pathogenic:1

Jun 10, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp2148Asn variant in CDH23 has been previously reported in 1 individual with Usher syndrome who was compound heterozygous with p.Trp2811* (Bonnet 2016). It has also been reported in 4 additional individuals with hearing loss without evidence of retinitis pigmentosa and segregated in four affected relatives (Astuto 2002, de Brouwer 2003, Pennings 2004, Schultz 2003). In one study, the variant was identified in one Dutch patient who was homozygous, and in an American patient who was compound heterozygous with p.R2608H (reported as uncertain and likely benign in ClinVar) (Astuto 2002). In another large family with hearing loss, the p.Asp2148Asn variant was identified in four family members with hearing loss; two siblings were homozygous and two other individuals were compound heterozygous (with p.D1341N) (de Brouwer 2003, Pennings 2004). The variant was also reported in two siblings with hearing loss who were compound heterozygous with p.Arg1746Gln (Schultz 2011). This variant has been identified in 0.01% (25/128344) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss, and there could be a risk for Usher syndrome associated with this variant when present in compound heterozygosity with a loss of function variant as was reported in Bonnet 2016. ACMG/AMP criteria applied: PP1_Strong, PM3, PM2_Supporting, PP3. -

Retinal dystrophy

Pathogenic:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

T;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.8

.;M

PrimateAI

Uncertain

0.54

REVEL

Pathogenic

0.73

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

.;D

Vest4

0.90

MVP

0.87

ClinPred

0.71

GERP RS

5.3

Varity_R

0.62

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

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