Gene Validity Curation

DSP - hypertrophic cardiomyopathy

Gene: DSP (HGNC:3052)
Classification - 04/07/2020
Disease: hypertrophic cardiomyopathy (MONDO_0005045)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Hypertrophic Cardiomyopathy EP
Evidence Summary: The relationship between DSP and Hypertrophic Cardiomyopathy (Autosomal Dominant) was re-evaluated using the ClinGen Clinical Validity Framework as of 10/30/2019. Although there have been two probands/families reported with variants in DSP and displayed HCM, both of these cases have conflicting sarcomeric variants that are likely responsible for the phenotypes observed. The authors of these papers also do not mention an association between the gene and disease in question. Experimentally, the only evidence to support DSP's involvement is the expression in the heart. This alone is not enough evidence to convincingly associate the gene-disease relationship. Therefore, no convincing evidence for a causal role for DSP in Autosomal Dominant Hypertrophic Cardiomyopathy has been reported. However, no convincing evidence has emerged that directly contradicts the gene-disease relationship.
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 2
0
0
Waldmüller S et al. 2015 Oct (PMID:25979592); De Bortoli M et al. 2017 Oct (PMID:28699631);
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) 0
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0
Lyon RC et al. 2014 Mar 1 (PMID:24108106);
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 0 0 0 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)
No Classification
10/30/2019
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
No Known Disease Relationship
10/30/2019
REASON(S) FOR CHANGE
There is no convincing evidence to associate DSP with HCM in either human probands or experimental models.
EXPERT CURATION (DATE)
No Known Disease Relationship
04/07/2020
EVIDENCE SUMMARY
The relationship between DSP and Hypertrophic Cardiomyopathy (Autosomal Dominant) was re-evaluated using the ClinGen Clinical Validity Framework as of 10/30/2019. Although there have been two probands/families reported with variants in DSP and displayed HCM, both of these cases have conflicting sarcomeric variants that are likely responsible for the phenotypes observed. The authors of these papers also do not mention an association between the gene and disease in question. Experimentally, the only evidence to support DSP's involvement is the expression in the heart. This alone is not enough evidence to convincingly associate the gene-disease relationship. Therefore, no convincing evidence for a causal role for DSP in Autosomal Dominant Hypertrophic Cardiomyopathy has been reported. However, no convincing evidence has emerged that directly contradicts the gene-disease relationship.