rs397517349

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM3PP1PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The variant c.6614C>T (NM_022124.6(CDH23):c.6614C>T (p.Pro2205Leu)) in CDH23 is a missense variant predicted to cause substitution of proline by leucine at amino acid 2205 (p.Pro2205Leu). The highest population minor allele frequency in gnomAD v4.0.0 is 0.000002920 (8/1179896 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.342, which is neither above nor below the thresholds predicting a damaging or benign impact on CDH23 function. This variant has been detected in at least 8 individuals with autosomal recessive hearing loss. All of these individuals were homozygous for the variant (1.0 pts; PMIDs: 28501645, 32747562 & LMM Internal Data (SCV000062934.5); PM3). There was a common haplotype found between five affected individuals from three families, one of which had three affected siblings, including a set of twins. Personal communication confirmed the three siblings were sequenced; however, it was not apparent whether the twins were dizygotic or monozygotic and therefore only one twin was counted toward segregation (PP1_Supporting; 28501645). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_Supporting, PM3, PP1_Supporting; Version 2; 11/15/23). LINK:https://erepo.genome.network/evrepo/ui/classification/CA137541/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:5U:5

Conservation

PhyloP100: 6.12

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

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

PM3

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

PP1

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.6614C>T	p.Pro2205Leu	missense_variant	Exon 48 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.6614C>T	p.Pro2205Leu	missense_variant	Exon 48 of 70	5	NM_022124.6	ENSP00000224721.9
CDH23	ENST00000642965.1 link	n.-95C>T		upstream_gene_variant				ENSP00000495222.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

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:

0.00

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

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248748

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461514

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111848

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000238

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:5Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Usher syndrome

Pathogenic:1Uncertain:1

Nov 15, 2023

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The variant c.6614C>T (NM_022124.6(CDH23):c.6614C>T (p.Pro2205Leu)) in CDH23 is a missense variant predicted to cause substitution of proline by leucine at amino acid 2205 (p.Pro2205Leu). The highest population minor allele frequency in gnomAD v4.0.0 is 0.000002920 (8/1179896 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.342, which is neither above nor below the thresholds predicting a damaging or benign impact on CDH23 function. This variant has been detected in at least 8 individuals with autosomal recessive hearing loss. All of these individuals were homozygous for the variant (1.0 pts; PMIDs: 28501645, 32747562 & LMM Internal Data (SCV000062934.5); PM3). There was a common haplotype found between five affected individuals from three families, one of which had three affected siblings, including a set of twins. Personal communication confirmed the three siblings were sequenced; however, it was not apparent whether the twins were dizygotic or monozygotic and therefore only one twin was counted toward segregation (PP1_Supporting; 28501645). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_Supporting, PM3, PP1_Supporting; Version 2; 11/15/23).

Jun 05, 2023

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.6614C>T (p.Pro2205Leu) results in a non-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 4e-06 in 248748 control chromosomes (gnomAD v2), absent in 316 control individuals from Middle Eastern (gnomAD v3) and absent in 1309 Palestinian controls (Rayyan _2020). c.6614C>T has been reported in the literature in multiple individuals affected with Non-syndromic hearing loss, including being seen phase unknown along with a VUS missense in a sporadic case (Sloan_Heggen_2016), in homozygous state in 5 patients from 3 consanguineous pedigrees in Qatar (Alkowari_2017), and in homozygous state in 2 patients from 2 Palestinian families (Rayyan _2020). Haplotype analysis of the patients revealed a same haplotype across those patients from Qatar, which support a common ancestor in those patients or a founder effect of this variant (Alkowari_2017). 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: 28501645, 29048421, 32747562, 26969326). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 among which four (including the ClinGen Hearing Loss Variant Curation Expert Panel) classified the variant as VUS, and one as likely pathogenic. Some submitters classifying the variant as uncertain significance cited the expert panel assertion and cited overlapping but not identical evidence captured in the context of this ascertainment. Based on the additional emerging evidence outlined above, the variant was classified as pathogenic.

not provided

Pathogenic:1Uncertain:1

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Nov 25, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 25356970, 34426522, 31860473, 34338889, 32747562, 26969326, 38844983, 38517009, 38378725, 28501645)

Autosomal recessive nonsyndromic hearing loss 12

Pathogenic:1Uncertain:1

Aug 01, 2020

King Laboratory, University of Washington

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

CDH23 c.6614C>T, p.E1071K alters a highly conserved residue of CDH23. The variant is homozygous in 3 children from 2 Palestinian families with moderate pre-lingual hearing loss (Abu Rayyan 2020). It was found also in 6 Palestinian children in compound heterozygosity with CDH23 c.1675C>T. The variant is absent from 1300 Palestinian controls and from gnomAD v2.1.1. This variant was previously interpreted as a VUS by the Expert Panel due to few Arab population controls. We suggest reclassification to LP given perfect co-segregation with hearing loss in additional families (both as a homozygote and as a compound heterozygote) and its absence from 1300 ancestry-matched controls

Aug 23, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Pituitary adenoma 5, multiple types

Pathogenic:1

Mar 14, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Usher syndrome type 1D

Pathogenic:1

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Uncertain:1

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Overall WES conclusion for patient, including all identified alterations: Uncertain

Rare genetic deafness

Uncertain:1

Feb 02, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Pro2205Leu variant in CDH23 has been reported in 3 individuals with hearing loss and 1 individual with Usher syndrome, 3 of whom were of Middle Eastern ancestry (Syrian, Saudi Arabian, Kuwaiti; Sloan-Heggen 2016, LMM data). Of the three individuals with hearing loss, one was homozygous, one individual was heterozygous, and one was compound heterozygous with a second CDH23 variant of uncertain significance. The individual with Usher syndrome was homozygous for a pathogenic variant in another gene that could account for the disease. This variant was absent from large population studies, though none of these studies specify frequency data for individuals of Middle Eastern ancestry. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.073

T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.71

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.0

.;M

PhyloP100

6.1

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.0

.;.

Sift

Pathogenic

0.0

.;.

Sift4G

Pathogenic

0.0

D;.

Vest4

0.85

ClinPred

0.97

GERP RS

5.1

Varity_R

0.61

gMVP

0.65

Mutation Taster

=21/79

disease causing

(source)

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

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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