10-71791167-C-T

Position:

chr10-71791167-C-T

Variant summary

Our verdict is Pathogenic. Variant got 4 ACMG points: 4P and 0B. PP3PP1PM3

This summary comes from the ClinGen Evidence Repository: The c.6085C>T variant in CDH23 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 2029 (p.Arg2029Trp). The highest population minor allele frequency in gnomAD v2.1.1 is 0.02% (3/17816 alleles) in the East Asian population. (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in many individuals with hearing loss or deafness, without any reported vision loss or evidence of retinopathy. Of those individuals, over 10 were homozygous or compound heterozygous for the variant and a pathogenic or likely pathogenic and many of those were confirmed in trans (6.75 PM3_Very Strong points, PMID:35020051, 25963016, 22899989, 17850630). The variant has been reported to segregate with hearing loss in 1 affected family member from 1 family (PP1_Supporting; PMID:22899989, 17850630). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VeryStrong, PP3, PP1. (VCEP specifications version 2; 06.26.2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5545996/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 1.83

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 4 ACMG points.

PM3

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

PP1

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

PP3

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.6085C>T	p.Arg2029Trp	missense_variant	47/70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.6085C>T	p.Arg2029Trp	missense_variant	47/70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000244

AC:

AN:

245426

Hom.:

AF XY:

0.0000375

AC XY:

AN XY:

133234

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000168

Gnomad SAS exome

AF:

0.0000668

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1459914

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726070

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00116

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2029 of the CDH23 protein (p.Arg2029Trp). This variant is present in population databases (rs750880909, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness (PMID: 17850630, 22899989, 25963016). 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: 446446). 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) has been performed at Invitae 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25587757, 26763877, 32027099, 34599366, 35020051, 17850630, 22899989, 25963016) -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 26, 2024

- -

Pituitary adenoma 5, multiple types

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 31, 2024

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jun 26, 2023

The c.6085C>T variant in CDH23 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 2029 (p.Arg2029Trp). The highest population minor allele frequency in gnomAD v2.1.1 is 0.02% (3/17816 alleles) in the East Asian population. (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in many individuals with hearing loss or deafness, without any reported vision loss or evidence of retinopathy. Of those individuals, over 10 were homozygous or compound heterozygous for the variant and a pathogenic or likely pathogenic and many of those were confirmed in trans (6.75 PM3_Very Strong points, PMID: 35020051, 25963016, 22899989, 17850630). The variant has been reported to segregate with hearing loss in 1 affected family member from 1 family (PP1_Supporting; PMID: 22899989, 17850630). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VeryStrong, PP3, PP1. (VCEP specifications version 2; 06.26.2023). -

Usher syndrome type 1D

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 10, 2024

Based on the classification scheme VCGS_Germline_v1.3.5, 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) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (61 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4) (highest allele frequency: 88 heterozygote, 1 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic for non-syndromic genetic hearing loss by the ClinGen Hearing Loss Variant Curation Expert Panel (ClinVar). In addition, it has been reported as homozygous and compound heterozygous with other missense in individuals affected with non-syndromic hearing loss (PMID: 35020051, 25963016, 22899989). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Autosomal recessive nonsyndromic hearing loss 12

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center

Jul 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;D

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Pathogenic

3.9

.;H

PrimateAI

Uncertain

0.54

REVEL

Pathogenic

0.70

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

.;D

Vest4

0.96

MutPred

0.92

Loss of catalytic residue at R2029 (P = 0.1277);Loss of catalytic residue at R2029 (P = 0.1277);

MVP

0.89

ClinPred

0.88

GERP RS

5.0

Varity_R

0.60

gMVP

0.80

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

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