Gene Validity Curation

PCDH19 - epilepsy

Gene: PCDH19 (HGNC:14270)
Classification - 09/04/2018
Disease: epilepsy (MONDO_0005027)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Epilepsy
Evidence Summary: The PCDH19 gene has been associated with X-linked epilepsy. Variants in PCDH19 have been reported in humans as early as 2008. Initially, the phenotypic description was that of intellectual disability and seizures with onset in the later part of infancy affecting girls. Subsequently, a broader spectrum of epilepsy phenotypes has emerged, including affected mosaic males. At least 11 variants (missense and de novo) were curated from two publications (19214208, 21480887). While there is no experimental support directly linking the gene to epilepsy, there is reasonable biological plausibility and the mechanism of the unusual sparing of the hemizygous condition has robust experimental support. In summary, there is definitive evidence to support this gene-disease association, replicated over more than a decade at the time of this curation. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 9/4/18 (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 10
12
12
Depienne C et al. 2009 Feb (PMID:19214208); Specchio N et al. 2011 Jul (PMID:21480887);
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
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
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) 0

 


 

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 12 0 12 YES
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)
Definitive
10/03/2019
EXPERT CURATION (DATE)
Definitive
09/04/2018
EVIDENCE SUMMARY
The PCDH19 gene has been associated with X-linked epilepsy. Variants in PCDH19 have been reported in humans as early as 2008. Initially, the phenotypic description was that of intellectual disability and seizures with onset in the later part of infancy affecting girls. Subsequently, a broader spectrum of epilepsy phenotypes has emerged, including affected mosaic males. At least 11 variants (missense and de novo) were curated from two publications (19214208, 21480887). While there is no experimental support directly linking the gene to epilepsy, there is reasonable biological plausibility and the mechanism of the unusual sparing of the hemizygous condition has robust experimental support. In summary, there is definitive evidence to support this gene-disease association, replicated over more than a decade at the time of this curation. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 9/4/18 (SOP Version 6).