Table 1.

Genes Implicated in HCM

GeneProteinFunctionTolerance to Variation
Missense (Z Score)LoF (pLI)
Established causal gene HCM (large families)
MYH7β-Myosin heavy chainATPase activity, force generation6.540.00
MYBPC3Myosin-binding protein CCardiac contraction0.690.00
TNNT2Cardiac troponin TRegulator of actomyosin interaction1.540.01
TNNI3Cardiac troponin IInhibitor of actomyosin interaction1.880.17
TPM1α-TropomyosinPlaces the troponin complex on cardiac actin3.420.80
ACTC1Cardiac α-actinActomyosin interaction5.250.95
MYL2Regulatory myosin light chainMyosin heavy chain 7–binding protein0.860.02
MYL3Essential myosin light chainMyosin heavy chain 7–binding protein0.750.89
CSRP3Cysteine- and glycine-rich protein 3Muscle LIM protein (MLP), a Z disk protein−0.660.00
Likely causal genes for HCM (small families)
FHL1Four-and-a-half LIM domains 1Muscle development and hypertrophy1.290.92
MYOZ2Myozenin 2 (calsarcin 1)Z disk protein0.030.02
PLNPhospholambanRegulator of sarcoplasmic reticulum calcium0.570.11
TCAPTcap (telethonin)Titin capping protein0.450.08
TRIM63Muscle ring finger protein 1E3 ligase of proteasome ubiquitin system0.020.00
TTNTitinSarcomere function−5.480.00
Genes associated with HCM (small families and sporadic cases)
ACTN2Actinin, α2Z disk protein1.761.0
ANKRD1Ankyrin repeat domain 1A negative regulator of cardiac genes−0.010.00
CASQ2Calsequestrin 2Calcium-binding protein−1.080.00
CAV3Caveolin 3A caveolae protein1.190.34
JPH2Junctophilin-2Intracellular calcium signaling3.930.01
LDB3Lim domain binding 3Z disk protein0.320.00
MYH6Myosin heavy chain αSarcomere protein expressed at low levels in the adult human heart2.870.00
MYLK2Myosin light chain kinase 2Phosphorylate myosin light chain 20.730.22
NEXNNexilinZ disc protein−1.320.00
TNNC1Cardiac troponin CCalcium-sensitive regulator of myofilament function2.220.51
VCLVinculinZ disk protein3.110.99
  • The Z score for each gene reflects deviation of the observed variants in the ExAC database from the expected number. A higher positive Z score indicates that the gene is intolerant to variation. Likewise, pLI indicates probability of intolerance to LoF variants with 1 indicating total intolerance. HCM indicates hypertrophic cardiomyopathy; and LoF, loss of function.