GeneBe

CDH3

protein-coding

cadherin 3, the group of Type I classical cadherins

Gene summary

This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. This gene is located in a gene cluster in a region on the long arm of chromosome 16 that is involved in loss of heterozygosity events in breast and prostate cancer. In addition, aberrant expression of this protein is observed in cervical adenocarcinomas. Mutations in this gene are associated with hypotrichosis with juvenile macular dystrophy and ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome (EEMS). [provided by RefSeq, Nov 2015]

MANE transcript

NM_001793.6

Inheritance

AR

ClinVar variants

P:60U:361B:244

Top phenotype

Hypotrichosis, congenital, with juvenile macular dystrophy; Ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr16:68,636,189-68,727,468

External References & Databases

Ensembl (ENSG00000062038)NCBI Gene (1001)OMIM (114021)HGNC:1762GenCCUniProt (P22223)AlphaFoldClinVar (CDH3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~91.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital hypotrichosis with juvenile macular dystrophyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011107

Submitter: G2P

congenital hypotrichosis with juvenile macular dystrophySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011107

Submitter: Orphanet

congenital hypotrichosis with juvenile macular dystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011107

Submitter: Labcorp Genetics (formerly Invitae)

EEM syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009155

Submitter: ClinGen

The CDH3 gene was first reported in relation to autosomal recessive congenital hypotrichosis with juvenile macular dystrophy (HJMD) in 2001 (Sprecher et al., PMID: 11544476). Subsequently, it was reported in relation to autosomal recessive ectodermal dysplasia, ectrodactyly, and macular dystrophy (EEM) in 2005 (Kjaer et al., PMID: 15805154). Both HJMD and EEM are rare, and their common features are sparse hair and macular dystrophy of the retina. Only EEM syndrome shows the additional hand/foot malformation. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism AND inheritance pattern. The phenotypic variability of EEM may include JHMD and mild hand/foot malformation is a relative common finding in the general population. Therefore, HJMD (OMIM #601553) and EEM (OMIM #225280) have been lumped into one disease entity represented by EEM. Eight variants (missense, nonsense, frameshift, canonical splicing) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be LOF. This gene-disease association is also supported by expression studies showing P-cadherin encoded by CDH3 in hair follicle placode, pigmented epithelium of the retina, and apical ectodermal ridge in the limb bud (Shimomura et al., PMID: 18199584). In summary, CDH3 is definitively associated with autosomal recessive ectodermal dysplasia, ectrodactyly, and macular dystrophy (EEM). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

EEM syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009155

Submitter: Ambry Genetics

EEM syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009155

Submitter: Labcorp Genetics (formerly Invitae)

EEM syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009155

Submitter: G2P

EEM syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009155

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hypotrichosis, congenital, with juvenile macular dystrophy; Ectodermal dysplasia, ectrodactyly, and macular dystrophy syndromeAR

Manifestation: Dermatologic; Musculoskeletal; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Heterozygotes may display subtle effects

Refs: 13372143; 10420194; 11544476; 12445216; 15805154; 20140736; 22140374; 22348569; 23143461Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDH3 variants in ClinVar

15 Conditions Cataloged
not providedTotal: 722
not specifiedTotal: 137
Inborn genetic diseasesTotal: 105
EEM syndromeTotal: 79
CDH3-related disorderTotal: 43
Congenital hypotrichosis with juvenile macular dystrophyTotal: 19
Retinal dystrophyTotal: 19
Hypotrichosis with juvenile macular dystrophyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001793.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
7
clinvar
216
clinvar
1
clinvar
 224
missense
1
clinvar
5
clinvar
348
clinvar
27
clinvar
 381
nonsense
7
clinvar
4
clinvar
1
clinvar
 12
start loss
1
clinvar
 1
frameshift
17
clinvar
7
clinvar
3
clinvar
 27
splice donor/acceptor (+/-2bp)
6
clinvar
12
clinvar
2
clinvar
 20
Total31293612431665

Highest pathogenic variant AF is 0.000044466397

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001793.6RefSeqNP_001784.216MANE Select
ENST00000264012.9EnsemblENSP00000264012.416MANE Select
NM_001317195.3RefSeqNP_001304124.116Standard
NM_001317196.2RefSeqNP_001304125.114Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cell adhesion molecules (CAMs) - Homo sapiens (human)
  • Hair Follicle Development- Induction (Part 1 of 3)
  • Overview of nanoparticle effects
  • EGFR1
  • Cell-cell junction organization

Biological Process

  • cell morphogenesis
  • retina homeostasis
  • cell-cell junction assembly
  • cell adhesion
  • homophilic cell adhesion via plasma membrane adhesion molecules

Molecular Function

  • molecular_function
  • calcium ion binding
  • cytoskeletal protein binding
  • protein homodimerization activity
  • cadherin binding

Cellular Component

  • cytoplasm
  • plasma membrane
  • cell-cell adherens junction
  • cell surface
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000264012
Coding exons
16
Length
86428
Individuals with no LoFs
125697
Homozygous LoFs
0
Heterozygous LoFs
51
Defined
125748
p
0.000203
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.07984684730.9900.00002935434
Missense (PolyPhen)187191.410.976982205
Synonymous-0.8282172021.070.00001411676
Loss of Function2.242135.40.5930.00000185412

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000330.00033rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000200.00020rare
South Asian0.000460.00046rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types.;
Disease
DISEASE: Hypotrichosis congenital with juvenile macular dystrophy (HJMD) [MIM:601553]: A disorder characterized by congenital hypotrichosis, early hair loss, and severe degenerative changes of the retinal macula that culminate in blindness during the second to third decade of life. {ECO:0000269|PubMed:11544476, ECO:0000269|PubMed:12445216}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome (EEMS) [MIM:225280]: A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. It is an autosomal recessive condition characterized by features of ectodermal dysplasia such as sparse eyebrows and scalp hair, and selective tooth agenesis associated with macular dystrophy and ectrodactyly. {ECO:0000269|PubMed:15805154}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0997

Intolerance Scores

LoFtool
0.729
RVIS EVS
-0.1
RVIS percentile EVS
45.66

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.788

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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