rs756147087

Positions:

chr10-71705043-G-A

Variant summary

Our verdict is Pathogenic. Variant got 5 ACMG points: 5P and 0B. PM3PM5PP3

This summary comes from the ClinGen Evidence Repository: The p.Glu956Lys variant in CDH23 is a missense variant predicted to cause substitution of glutamic acid to lysine at amino acid 956. The highest population minor allele frequency in gnomAD v3.1.2 is 0.02895% (12/41444) in African/African American population which is greater than the PM2_Supporting thresholds defined by the ClinGen Hearing Loss Expert Panel (≤0.007%) and less than the BS1_supporting MAF of ≥0.0007 (0.07%) for autosomal recessive disorders (no codes met). The computational predictor REVEL produced a score of 0.616, which was just below the threshold to automatically apply PP3, but the Expert Panel decided to apply PP3 based upon manual review of alignments to examine homology. This variant has been detected in at least six probands with hearing loss without evidence of retinal disease (5 PM3_Very Strong points, PMID:26763877,25963016, 22899989, Invitae Internal Data (SCV001228538.3)). Of those individuals, four harbored the p.Pro240Leu pathogenic variant in CDH23 with three individuals confirmed in trans (PMID 25963016, 22899989). The fifth individual harbored the p.Asp645Gly variant in CDH23, but phasing was not performed (PMID 25963016). The sixth proband carried a second pathogenic CDH23 variant in trans (Invitae Internal Data). 1 different missense variant, c.2867A>G (p.Glu956Gly) ClinVar Variation ID:1180655, in the same codon has been classified as likely pathogenic for AR sensorineural hearing loss by two submitters in ClinVar (PM5). In summary, this variant meets the criteria to be classified as pathogenic for AR hearing loss based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PP3, PM3_Very Strong, PM5. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA5544361/MONDO:0020678/005

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:8U:1

Conservation

PhyloP100: 9.96

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 5 ACMG points.

PM3

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

PM5

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 link	c.2866G>A	p.Glu956Lys	missense_variant	25/70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171930.2 link	c.2866G>A	p.Glu956Lys	missense_variant	25/32		NP_001165401.1	Q9H251A0A087WYR8Q6P152
CDH23	NM_001171931.2 link	c.2866G>A	p.Glu956Lys	missense_variant	25/26		NP_001165402.1	Q9H251Q8N5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.2866G>A	p.Glu956Lys	missense_variant	25/70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000325

AC:

AN:

246242

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

134592

show subpopulations

Gnomad AFR exome

AF:

0.000265

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000560

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460396

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726520

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000290

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 956 of the CDH23 protein (p.Glu956Lys). This variant is present in population databases (rs756147087, gnomAD 0.03%). This missense change has been observed in individual(s) with deafness (PMID: 22899989, 25963016; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 444219). 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	Mar 15, 2024	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: 28714951, 26763877, 31785789, 26346818, 35020051, 22899989, 25963016, 30303587) -

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

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 31, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM3_VeryStrong -

Sensorineural hearing loss disorder

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jun 27, 2023

The p.Glu956Lys variant in CDH23 is a missense variant predicted to cause substitution of glutamic acid to lysine at amino acid 956. The highest population minor allele frequency in gnomAD v3.1.2 is 0.02895% (12/41444) in African/African American population which is greater than the PM2_Supporting thresholds defined by the ClinGen Hearing Loss Expert Panel (less than or equal to 0.007%) and less than the BS1_supporting MAF of greater than or equal to 0.0007 (0.07%) for autosomal recessive disorders (no codes met). The computational predictor REVEL produced a score of 0.616, which was just below the threshold to automatically apply PP3, but the Expert Panel decided to apply PP3 based upon manual review of alignments to examine homology. This variant has been detected in at least six probands with hearing loss without evidence of retinal disease (5 PM3_Very Strong points, PMID: 26763877,25963016, 22899989, Invitae Internal Data (SCV001228538.3)). Of those individuals, four harbored the p.Pro240Leu pathogenic variant in CDH23 with three individuals confirmed in trans (PMID 25963016, 22899989). The fifth individual harbored the p.Asp645Gly variant in CDH23, but phasing was not performed (PMID 25963016). The sixth proband carried a second pathogenic CDH23 variant in trans (Invitae Internal Data). 1 different missense variant, c.2867A>G (p.Glu956Gly) ClinVar Variation ID:1180655, in the same codon has been classified as likely pathogenic for AR sensorineural hearing loss by two submitters in ClinVar (PM5). In summary, this variant meets the criteria to be classified as pathogenic for AR hearing loss based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PP3, PM3_Very Strong, PM5. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023) -

Pituitary adenoma 5, multiple types

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 02, 2024

- -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

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

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

T;T;D;.;T;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

4.1

.;.;H;.;.;.

PrimateAI

Uncertain

0.71

REVEL

Uncertain

0.62

Sift4G

Pathogenic

0.0

D;D;.;D;D;.

Polyphen

1.0

.;.;D;.;.;.

Vest4

0.94

MVP

0.92

ClinPred

0.99

GERP RS

5.5

Varity_R

0.60

gMVP

0.81

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