Gene Validity Classification Summary

Gene/Disease Pair:

PDLIM3 : hypertrophic cardiomyopathy

HGNC:20767 | MONDO_0005045
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hypertrophic Cardiomyopathy EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max 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
0.1
0.1
Bagnall RD et al. 2010 Dec 3 (PMID:20801532);
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 Evidence of segregation in one or more families   Sequencing Method 0-3 3
 
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total 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) 0.1
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
1
Protein Interaction 0.5 0 - 2 0.5
Xia H et al. 1997 Oct 20 (PMID:9334352);
Expression 0.5 0 - 2 0.5
Xia H et al. 1997 Oct 20 (PMID:9334352);
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) 1

 


 

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 0.1 1 1.1 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
08/06/2018
EXPERT CURATION (DATE)
Limited
08/06/2018
EVIDENCE SUMMARY
The PDLIM3 gene has been associated with HCM in 2 probands in 2 publications. One variant of unknown significance and 1 multi-exon deletion have been reported in humans with HCM. PDLIM3 was first associated with HCM in humans in 2010 (Bagnall et al, 2010, PMID: 20801532). PDLIM is expressed in heart and interacts with ACTN2. However, there is no known mechanism through which PDLIM causes HCM. In summary, there is limited evidence to support this gene-disease association with HCM. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on November 1, 2016.