10-71812826-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received -3 ACMG points: 1P and 4B. PP3BS2

This summary comes from the ClinGen Evidence Repository: The c.9569C>T variant (NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val)) in CDH23 is a missense variant predicted to cause substitution of alanine by valine at amino acid 3190 (p.Ala3190Val). The highest minor allele frequency in gnomAD v4.0.0 is 694/1179698 alleles (0.0005517), in the European (non-Finnish) population (no population codes met). This variant has been observed in a homozygous state in one parent reported to have no features of Usher syndrome (BS2; Invitae internal data; ClinVar SCV001110059.2). The computational predictor REVEL gives a score of 0.836, which is above the Hearing Loss VCEP threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). The variant was found in a compound heterozygous state with a deletion of exon 29, a variant which was not able to be confirmed by aCGH (PMID:25404053). The variant was also found in an unknown phase with p.Arg3206Cys (c.9616C>T), a variant of uncertain significance, in an affected patient with nonsyndromic hearing loss (PMID:27068579; PM3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: BS2, PP3 (Version 2; 11/15/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA137643/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00050 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:8B:1

Conservation

PhyloP100: 7.85

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 12
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1D
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CDH23 links:

LOC124902446 (HGNC:):

LOC124902446 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received -3 ACMG points.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.9569C>T	p.Ala3190Val	missense_variant	Exon 68 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.9569C>T	p.Ala3190Val	missense_variant	Exon 68 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000339

AC:

AN:

247998

AF XY:

0.000379

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000378

Gnomad ASJ exome

AF:

0.000698

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000543

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.000500

AC:

731

AN:

1461206

Hom.:

Cov.:

AF XY:

0.000488

AC XY:

355

AN XY:

726848

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33472

American (AMR)

AF:

0.000403

AC:

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.000727

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86134

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000587

AC:

652

AN:

1111650

Other (OTH)

AF:

0.000613

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

115

154

192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000361

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41464

American (AMR)

AF:

0.000262

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000617

AC:

AN:

68048

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000518

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000237

AC:

ExAC

AF:

0.000273

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000773

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:8Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jul 10, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with nonsyndromic hearing loss, along with a second variant with unknown phase in published literature (PMID: 27068579); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30245029, 32387678, 31445392, 36672845, 27068579, 25404053) -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CDH23: PP3 -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2

Sep 12, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ala3190Val variant in CDH23 has been reported in 1 individual with Usher s yndrome who also had a duplication of exon 29 in CDH23 that is of uncertain sign ificance (Aparisi 2014), and in 1 individual with hearing loss who also had the p.Arg3206Cys variant of uncertain significance in CDH23 (Sommen 2016). The p.Ala 3190Val variant has also been identified by our laboratory in the heterozygous s tate in 3 individuals with hearing loss; however, a variant affecting the remain ing copy of CDH23 was not identified in any of these individuals. This variant h as been identified in 0.08% (8/10122) of Ashkenazi Jewish chromosomes and 0.05% (64/126200) European chromosomes by Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org; dbSNP rs111033536). Although this variant has been se en in the general population, its frequency is not high enough to rule out a pat hogenic role. Computational prediction tools and conservation analyses suggest t hat this variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, the clinical significance of t he p.Ala3190Val variant is uncertain. -

Sep 13, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CDH23 c.9569C>T (p.Ala3190Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 247998 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (0.00034 vs 0.0032), allowing no conclusion about variant significance. c.9569C>T has been reported in the literature in individuals with hearing loss (e.g., Aparisi_2014, Sommen_2016, Clabout_2022), however without strong evidence of causality in all cases (e.g., lack of a second confirmed CDH23 allele and/or segregation/phase not determined). This variant was also listed as an expert curated classification of "likely pathogenic" in the Deafness Variation Database (DVD) (e.g., Azaiez_2018) and cited by others (e.g., Chen_2019). These reports therefore do not provide unequivocal conclusions about association of the variant with Usher Syndrome. 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: 25404053, 30245029, 27068579, 36672845, 31445392). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=6; Likely pathogenic, n=1; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hearing impairment

Pathogenic:1

Apr 12, 2021

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS1_Moderate, PM2_Moderate, PP3_Supporting -

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

Uncertain:1

May 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDH23-related disorder

Uncertain:1

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CDH23 c.9569C>T variant is predicted to result in the amino acid substitution p.Ala3190Val. This variant has been reported in the presumed compound heterozygous state with a duplication of exon 29 (that was not confirmed by orthogonal method) in an individual with Usher syndrome (Aparisi et al. 2014. PubMed ID: 25404053). It has also been reported together with another variant of uncertain significance in CDH23 in patient with hearing loss (Table S2, Sommen et al. 2016. PubMed ID: 27068579) and in the heterozygous state without a second disease-causing variant in another individual with non-syndromic hearing loss (NSHL) (Table A2, Clabout et al. 2022. PubMed ID: 36672845). Of note, this variant has also been observed in the homozygous state in a patient tested for Usher syndrome at PreventionGenetics who was also homozygous for a protein-truncating variant in the PCDH15 gene (internal data). This variant is reported in 0.068% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Pituitary adenoma 5, multiple types

Uncertain:1

Oct 30, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome

Uncertain:1

Nov 15, 2023

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The c.9569C>T variant (NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val)) in CDH23 is a missense variant predicted to cause substitution of alanine by valine at amino acid 3190 (p.Ala3190Val). The highest minor allele frequency in gnomAD v4.0.0 is 694/1179698 alleles (0.0005517), in the European (non-Finnish) population (no population codes met). This variant has been observed in a homozygous state in one parent reported to have no features of Usher syndrome (BS2; Invitae internal data; ClinVar SCV001110059.2). The computational predictor REVEL gives a score of 0.836, which is above the Hearing Loss VCEP threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). The variant was found in a compound heterozygous state with a deletion of exon 29, a variant which was not able to be confirmed by aCGH (PMID: 25404053). The variant was also found in an unknown phase with p.Arg3206Cys (c.9616C>T), a variant of uncertain significance, in an affected patient with nonsyndromic hearing loss (PMID: 27068579; PM3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: BS2, PP3 (Version 2; 11/15/2023). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0094

T;T;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.41

T;T;T;T

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

1.0

.;L;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.67

.;.;.;N

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

.;.;.;D

Sift4G

Pathogenic

0.0

D;.;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.83

MVP

0.89

MPC

0.18

ClinPred

0.12

GERP RS

5.8

Varity_R

0.37

gMVP

0.63

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over