Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ACTN2 : intrinsic cardiomyopathy

HGNC:164 | MONDO_0000591
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 0.1 0.1
Zimmerman RS et al. 2010 May (PMID:20474083);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Theis JL et al. 2006 Dec 29 (PMID:17097056); Chiu C et al. 2010 Mar 16 (PMID:20022194); Bagnall RD et al. 2014 Sep 16 (PMID:25224718); Girolami F et al. 2014 Dec (PMID:25173926); Jaafar N et al. 2015 Apr 7 (PMID:26779504); Xu J et al. 2015 Nov 17 (PMID:26573135); Zimmerman RS et al. 2010 May (PMID:20474083); Mohapatra B et al. 2003 Sep-Oct (PMID:14567970);
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) 4.6
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Bagnall RD et al. 2014 Sep 16 (PMID:25224718);
Protein Interaction 0.5 0 - 2 1
Vafiadaki E et al. 2014 Jul (PMID:24860983); Ziane R et al. 2010 Jan 12 (PMID:19943616);
Expression 0.5 0 - 2 0.5
Beggs AH et al. 1992 May 5 (PMID:1339456);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 0.5
Chiu C et al. 2010 Mar 16 (PMID:20022194);
Models Non-human model organism 2 0 - 4 4 2
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Gupta V et al. 2012 May (PMID:22253474);
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
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 4.6 4.5 9.1 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
ACTN2 was associated with hypertrophic cardiomyopathy in humans in 2006 (Theis et al, 2006, PMID 17097056) and dilated cardiomyopathy in 2010 (Zimmerman et al, 2010, PMID 20474083). Twelve unique heterozygous variants of unknown significance (11 missense, 1 frameshift), with little to no experimental evidence to support their pathogenicity, have been reported in ACTN2 in humans. Missense variants in this gene segregated with atypical HCM in one family (max LOD 2.8) (Chiu et al, 2010, PMID 20022194), diverse cardiac phenotypes including sudden death, LVNC, DCM, and ventricular fibrillation in a second family (related to the first based on haplotype analysis) (Bagnal et al, 2014, PMID 25224718), and with combinations of HCM, LVNC and arrhythmia in another family (14 segregations) (Girolami et al, 2014, PMID 25173926). The mechanism for disease is unknown. Case-control studies have found no increased frequency of rare ACTN2 variants in individuals with HCM, suggesting that much of the observed variation may be benign (Walsh et al, 2016, PMID 27532257). This gene-disease association is supported by the function of the protein (Bagnal et al, 2014, PMID 25224718), protein interaction with CSRP3 and SCN5A (Louis et al, 2007, PMID 9341203; Ziane et al, 2010, PMID 19943616; Vafiadaki et al, 2014, PMID 24860983), expression of the gene product (alpha actinin-2) in heart (Beggs et al, 1992, 1339456; Haywood et al, 2016, PMID 27287556), and rescue of a DCM phenotype in a zebrafish model (Gupta et al, 2012, PMID 22253474). In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. Based on curated literature, this gene can cause seemingly isolated left ventricular hypertrophy. Given the lack of constraint of ACTN2, classification of variants in this gene should be considered with care. This classification was approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on April 10, 2018. Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism underlying the disease entities: (1) Cardiomyopathy, dilated, 1AA, with or without LVNC (MIM: 612158) and (2) Cardiomyopathy, hypertrophic, 23, with or without LVNC (MIM: 612158). Note that both of these disease entities have the same MIM numbers, suggesting that they are part of the same condition. ACTN2 was curated for intrinsic cardiomyopathy based upon the variable cardiac presentations, including cardiomyopathies and arrhythmias, observed in large families with ACTN2 variants. For clinical management, all of the phenotypes are cardiovascular, and individuals should be monitored appropriately. Therefore, all of the disease entities have been lumped into one disease entity, Intrinsic cardiomyopathy.