Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PCDH15 : nonsyndromic genetic deafness

HGNC:14674 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 1
0
1.1
Yang T et al. 2013 Jun 14 (PMID:23767834);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 11
1.1
Ahmed ZM et al. 2003 Dec 15 (PMID:14570705); Zhan Y et al. 2015 Jul (PMID:25930172); Doucette L et al. 2009 May (PMID:19107147); Wang R et al. 2017 May (PMID:28281779); Chen Y et al. 2015 May 26 (PMID:26011067); Mutai H et al. 2013 Oct 28 (PMID:24164807); Yang T et al. 2013 Jun 14 (PMID:23767834); Chen DY et al. 2015 Oct (PMID:26279247); Ahmed ZM et al. 2008 Oct (PMID:18719945);
Segregation Evidence   Summed LOD Family Count 1.7 1.7  
Candidate gene sequencing 8.7 3
Ahmed ZM et al. 2003 Dec 15 (PMID:14570705); Zhan Y et al. 2015 Jul (PMID:25930172);
Exome/genome or all genes sequenced in linkage region 1.33 1
Wang R et al. 2017 May (PMID:28281779);
Total Summed LOD Score 10.03    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12 1
0
0
Xu XR et al. 2017 Feb (PMID:28292353);
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 2.8
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2 2 0.5
Mahendrasingam S et al. 2017 Oct 25 (PMID:29069081); Zhao B et al. 2014 Dec 03 (PMID:25467981);
Expression 0.5 0 - 2 5 2
Ahmed ZM et al. 2003 Dec 15 (PMID:14570705); Alagramam KN et al. 2001 Jan (PMID:11138007); Haywood-Watson RJ et al. 2006 Jul (PMID:16799054); Nishio SY et al. 2017 May (PMID:28263850); Ahmed ZM et al. 2006 Jun 28 (PMID:16807332);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 5 0 0
Zheng QY et al. 2005 Jan 01 (PMID:15537665); Alagramam KN et al. 2001 Jan (PMID:11138007); Kikkawa YS et al. 2008 Feb (PMID:18085631); Naoi K et al. 2009 Jan (PMID:19151506); Geng R et al. 2013 Mar 06 (PMID:23467356);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 2

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 2.8 2 4.8 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Limited
12/06/2018
EXPERT CURATION (DATE)
Limited
06/19/2018
EVIDENCE SUMMARY
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.