Gene Validity Curation

KLF10 - hypertrophic cardiomyopathy

Gene: KLF10 (HGNC:11810)
Classification - 08/01/2017
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 KLF10 gene has been associated with autosomal dominant hypertrophic cardiomyopathy using the ClinGen Clinical Validity Framework as of January 27, 2017. This association was made using Case-level data and Case-control data. At least 5 unique missense variants have been reported , and an additional variant that is predicted benign based on maximum allele frequency in the general population above the recommended cutoff for pathogenicity (Bos et al., 2012 PMID: 22234868). KLF10 was first associated with this disease in humans as early as 2012. The association was observed in only 6 probands from one publication (Bos et al., 2012 PMID: 22234868). No segregation data is available. The mechanism for disease is unclear, but predicted to be loss of function (LOF) from functional assays performed by Bos et al., 2012. This gene-disease association is supported by expression studies showing enhanced expression of KLF10 in skeletal muscle and heart (lesser expression in placenta and pancreas) (Subramaniam et al., 1995 PMID: 8532536; Jiang et al., 2010 PMID: 20201061), functional alterations in non-patient cells (Li et al., 2015 PMID: 26252173), and an animal model (KLF10 knockout mice, Rajamannan et al., 2007 PMID: 16888812 ). In summary, there is limited evidence to support this gene-disease association. 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 Expert Panel on August 1, 2017.
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 6
1.25
1.25
Bos JM et al. 2012 Jun (PMID:22234868);
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
0
Aggregate Variant Analysis 0-6 1
0
Walsh R et al. 2017 Dec 7 (PMID:28082330);
Total Genetic Evidence Points (Maximum 12) 1.25
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
Subramaniam M et al. 1995 Dec 11 (PMID:8532536); Jiang L et al. 2010 May (PMID:20201061); Li Q et al. 2015 Aug (PMID:26252173);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 2 0.5
Rajamannan NM et al. 2007 Feb 1 (PMID:16888812); Li Q et al. 2015 Aug (PMID:26252173);
Models Non-human model organism 2 0 - 4 4 1 2.5 2.5
Rajamannan NM et al. 2007 Feb 1 (PMID:16888812);
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) 4.5

 


 

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 1.25 4.5 5.75 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
11/15/2019
EXPERT CURATION (DATE)
Limited
08/01/2017
EVIDENCE SUMMARY
The KLF10 gene has been associated with autosomal dominant hypertrophic cardiomyopathy using the ClinGen Clinical Validity Framework as of January 27, 2017. This association was made using Case-level data and Case-control data. At least 5 unique missense variants have been reported , and an additional variant that is predicted benign based on maximum allele frequency in the general population above the recommended cutoff for pathogenicity (Bos et al., 2012 PMID: 22234868). KLF10 was first associated with this disease in humans as early as 2012. The association was observed in only 6 probands from one publication (Bos et al., 2012 PMID: 22234868). No segregation data is available. The mechanism for disease is unclear, but predicted to be loss of function (LOF) from functional assays performed by Bos et al., 2012. This gene-disease association is supported by expression studies showing enhanced expression of KLF10 in skeletal muscle and heart (lesser expression in placenta and pancreas) (Subramaniam et al., 1995 PMID: 8532536; Jiang et al., 2010 PMID: 20201061), functional alterations in non-patient cells (Li et al., 2015 PMID: 26252173), and an animal model (KLF10 knockout mice, Rajamannan et al., 2007 PMID: 16888812 ). In summary, there is limited evidence to support this gene-disease association. 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 Expert Panel on August 1, 2017.