GeneBe

PCDH15

protein-coding

protocadherin related 15, the group of Cadherin related|MicroRNA protein coding host genes

Gene summary

This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

Previous symbols:
  • USH1F
  • DFNB23

MANE transcript

NM_001384140.1

Inheritance

AR, Digenic

ClinVar variants

P:466U:809B:779

Top phenotype

Deafness, autosomal recessive 23; Usher syndrome, type 1F; Usher syndrome, type 1D

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr10:53,802,771-55,627,942

External References & Databases

Ensembl (ENSG00000150275)NCBI Gene (65217)OMIM (605514)HGNC:14674GenCCUniProt (Q96QU1)AlphaFoldClinVar (PCDH15)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~1,825.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Usher syndrome type 1FSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011186

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Usher syndrome type 1FDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011186

Submitter: G2P

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The relationship between PCDH15 and autosomal recessive nonsyndromic hearing loss (ARNSHL) was evaluated using the ClinGen Clinical Validity Framework as of 12/8/2017. The PCDH15 gene has previously been classified as Definitive for Usher syndrome by the ClinGen Hearing Loss Expert Panel. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, we have split curations for the disease entities of Usher syndrome and non-syndromic hearing loss. Variants in PCDH15 were first reported in humans with this disease as early as 2003 (Ahmed et al., PMID 14570705). There are many cases in the literature claiming non-syndromic hearing loss with PCDH15 variants however many of the variants were not scored due to lack of convincing evidence of pathogenicity or lack of information of phase. However, at least 4 unique variants (missense, in-frame indel, truncating nonsense, frameshift) with sufficient evidence to score reported in humans with sufficient electroretinography or age-dependent phenotyping to rule out Usher syndrome. These variants were detected in a large Pakistani family with non-syndromic hearing loss with no history of retinitis pigmentosa (RP) (age range 13-44) (Ahmed 2003 14570705); a Chinese family that was claimed to be non-consanguineous with non-syndromic HL (18 year old proband and 28 year old brother w/ HL) (Zhan 2015 25930172); a 21 y.o. male noted to have no other symptoms (Wang 2017 28281779). There were some patients described to have no ERG's conducted so Usher syndrome could not be ruled out (Yang 2013 23767834). This gene-disease association is supported by expression studies and protein interaction studies (PMIDs: 25467981, 16807332, 11138007, 28263850, 14570705). However, many of the cases do not provide ages for individuals which makes this scoring susceptible to including cases that may develop late-onset RP. Therefore, the association between PCDH15 and ARNSHL is Limited. This classification was approved by the ClinGen Hearing Loss Working Group on 6/19/2018.

Usher syndrome type 1DLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010984

Submitter: Natera

Usher syndrome type 1FDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011186

Submitter: Natera

autosomal recessive nonsyndromic hearing loss 23DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012293

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

autosomal recessive nonsyndromic hearing loss 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012293

Submitter: Labcorp Genetics (formerly Invitae)

Usher syndrome type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010168

Submitter: Orphanet

Usher syndrome type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010168

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 23; Usher syndrome, type 1F; Usher syndrome, type 1DAR/Digenic

Manifestation: Audiologic/Otolaryngologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: Inheritance of some conditions can be digenic, involving CDH23

Refs: 11398101; 14570705; 15537665; 17653769; 18719945; 19107147Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCDH15 variants in ClinVar

25 Conditions Cataloged
not providedTotal: 2891
Usher syndrome type 1FTotal: 908
Inborn genetic diseasesTotal: 334
Autosomal recessive nonsyndromic hearing loss 23Total: 324
not specifiedTotal: 270
Usher syndrome type 1DTotal: 200
Usher syndrome type 1Total: 139
PCDH15-related disorderTotal: 86

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001384140.1. 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
20
clinvar
712
clinvar
1
clinvar
 733
missense
1
clinvar
14
clinvar
757
clinvar
56
clinvar
9
clinvar
 837
nonsense
42
clinvar
61
clinvar
6
clinvar
 109
start loss
1
clinvar
1
clinvar
 2
frameshift
93
clinvar
143
clinvar
18
clinvar
 254
splice donor/acceptor (+/-2bp)
10
clinvar
101
clinvar
7
clinvar
1
clinvar
 119
Total146320809769102054

Highest pathogenic variant AF is 0.0001233174

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001384140.1RefSeqNP_001371069.137MANE Select
ENST00000644397.2EnsemblENSP00000495195.137MANE Select
NM_001142763.2RefSeqNP_001136235.134Standard
NM_001142764.2RefSeqNP_001136236.133Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
pcdh15aDanio rerio

Structure: neuromast hair cell

Quality: decreased functionality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • cell adhesion
  • homophilic cell adhesion via plasma membrane adhesion molecules
  • sensory perception of sound
  • photoreceptor cell maintenance
  • inner ear development

Molecular Function

  • calcium ion binding

Cellular Component

  • photoreceptor outer segment
  • extracellular region
  • integral component of plasma membrane
  • stereocilium
  • synapse

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000361849
Coding exons
33
Length
1825172
Individuals with no LoFs
125198
Homozygous LoFs
1
Heterozygous LoFs
549
Defined
125748
p
0.00219
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-1.6811961.04e+31.150.000054312747
Missense (PolyPhen)433379.091.14224666
Synonymous-1.874223761.120.00002063970
Loss of Function3.115282.50.6300.000004681011

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0120.012notable
Latino/Admixed American0.00170.0017notable
Ashkenazi Jewish0.00440.0044notable
East Asian0.00260.0026notable
Finnish0.000420.00042rare
European (Non-Finnish)0.00130.0013notable
South Asian0.00130.0013notable
Other0.00160.0016notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Calcium-dependent cell-adhesion protein. Essential for maintenance of normal retinal and cochlear function.;
Disease
DISEASE: Usher syndrome 1F (USH1F) [MIM:602083]: USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 is characterized by profound congenital sensorineural deafness, absent vestibular function and prepubertal onset of progressive retinitis pigmentosa leading to blindness. {ECO:0000269|PubMed:15660226, ECO:0000269|PubMed:22815625}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Usher syndrome 1D/F (USH1DF) [MIM:601067]: USH1DF patients are heterozygous for mutations in CDH23 and PCDH15, indicating a digenic inheritance pattern. {ECO:0000269|PubMed:15537665, ECO:0000269|PubMed:18719945}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 23 (DFNB23) [MIM:609533]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:14570705, ECO:0000269|PubMed:18719945, ECO:0000269|PubMed:28281779}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.178

Intolerance Scores

LoFtool
0.995
RVIS EVS
0.74
RVIS percentile EVS
86.35

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.0375

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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