Primary familial hypertrophic cardiomyopathy: genes and variants

Genes linked to Primary familial hypertrophic cardiomyopathy

• GLA: Alpha-galactosidase A

  It removes terminal alpha-galactose residues from glycosphingolipids during lysosomal degradation. Loss-of-function variants cause Fabry disease, with progressive accumulation of globotriaosylceramide-related lipids in vascular, renal, cardiac, and nervous tissues.

  5 disease-causing and 1 uncertain variants in GLA are linked to Primary familial hypertrophic cardiomyopathy.

• MYH7: Myosin-7

  Its beta-myosin motor converts ATP hydrolysis into force within cardiac and slow-skeletal-muscle sarcomeres. Pathogenic variants are major causes of hypertrophic and dilated cardiomyopathy and can also produce inherited skeletal myopathies.

  4 disease-causing and 4 uncertain variants in MYH7 are linked to Primary familial hypertrophic cardiomyopathy.

• ACTN2: Alpha-actinin-2

  It crosslinks actin at the sarcomeric Z-disc and organizes mechanical and signaling complexes in cardiac and skeletal muscle. Pathogenic variants can cause hypertrophic, dilated, or other inherited cardiomyopathies and occasional skeletal-muscle phenotypes.

  1 disease-causing and 497 uncertain variants in ACTN2 are linked to Primary familial hypertrophic cardiomyopathy.

• MYBPC3: Myosin-binding protein C, cardiac-type

  A cardiac thick-filament protein positioned in the cross-bridge region of striated muscle. It binds myosin and actin and helps tune contraction, while MYBPC3 variants are a leading genetic cause of hypertrophic cardiomyopathy.

  1 disease-causing and 6 uncertain variants in MYBPC3 are linked to Primary familial hypertrophic cardiomyopathy.

• JPH2: Junctophilin-2

  It anchors the sarcoplasmic reticulum close to transverse tubules, creating junctional membrane domains required for tightly coupled calcium entry and calcium release in heart muscle. Pathogenic variants can disrupt excitation-contraction coupling and cause hypertrophic or dilated cardiomyopathy and inherited arrhythmia phenotypes.

  1 disease-causing and 3 uncertain variants in JPH2 are linked to Primary familial hypertrophic cardiomyopathy.

• TNNI3: Troponin I, cardiac muscle

  It restrains cardiac actin-myosin interaction at low calcium and shifts position within the troponin complex when calcium binds, allowing contraction. Pathogenic variants can alter thin-filament calcium sensitivity and cause hypertrophic, restrictive, or dilated cardiomyopathy.

  1 disease-causing and 1 uncertain variants in TNNI3 are linked to Primary familial hypertrophic cardiomyopathy.

• KCNH2: Voltage-gated inwardly rectifying potassium channel KCNH2

  Its unusually rapid inactivation and slow deactivation shape the rapid delayed-rectifier current IKr, a major determinant of ventricular repolarization. Loss-of-function variants can prolong repolarization and cause long-QT syndrome, whereas gain-of-function variants can cause short-QT syndrome.

  1 disease-causing and 0 uncertain variants in KCNH2 are linked to Primary familial hypertrophic cardiomyopathy.

• MYH6: Myosin-6

  Its alpha-myosin motor contributes to ATP-dependent force generation in the cardiac sarcomere, particularly in atrial myocardium. Pathogenic variants can cause cardiomyopathy, congenital heart defects, and selected conduction-system disorders.

  0 disease-causing and 5 uncertain variants in MYH6 are linked to Primary familial hypertrophic cardiomyopathy.

Weakly linked (only a few uncertain records): LDB3, LMNA, MYL2, RBM20, ACTC1, ANKRD1, CSRP3, DES and 7 more.

Known disease-causing variants in Primary familial hypertrophic cardiomyopathy

Which prediction tools work for Primary familial hypertrophic cardiomyopathy

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 87 out of 100
• PolyPhen-2: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 83 out of 100
• AlphaMissense: 82 out of 100

Same protein, different disease

• Fabry disease is also caused by GLA variants; they fall mostly in different places as the Primary familial hypertrophic cardiomyopathy variants (320 disease-causing).
• Hypertrophic cardiomyopathy is also caused by MYH7 variants; they fall mostly in different places as the Primary familial hypertrophic cardiomyopathy variants (239 disease-causing).
• Dilated cardiomyopathy is also caused by MYH7 variants; they fall mostly in different places as the Primary familial hypertrophic cardiomyopathy variants (21 disease-causing).
• Primary dilated cardiomyopathy is also caused by MYH7 variants; they fall mostly in different places as the Primary familial hypertrophic cardiomyopathy variants (15 disease-causing).
• Myosin storage myopathy is also caused by MYH7 variants; they fall mostly in different places as the Primary familial hypertrophic cardiomyopathy variants (13 disease-causing).
• MYH7-related skeletal myopathy is also caused by MYH7 variants; they fall mostly in different places as the Primary familial hypertrophic cardiomyopathy variants (7 disease-causing).
• Hypertrophic cardiomyopathy is also caused by MYBPC3 variants; they fall mostly in different places as the Primary familial hypertrophic cardiomyopathy variants (19 disease-causing).
• Left ventricular noncompaction is also caused by MYBPC3 variants; they fall mostly in different places as the Primary familial hypertrophic cardiomyopathy variants (8 disease-causing).
• Hypertrophic cardiomyopathy is also caused by TNNI3 variants; they fall mostly in different places as the Primary familial hypertrophic cardiomyopathy variants (24 disease-causing).
• Cardiomyopathy, familial restrictive, 3 is also caused by TNNI3 variants; they fall mostly in different places as the Primary familial hypertrophic cardiomyopathy variants (9 disease-causing).
• Dilated cardiomyopathy 1FF is also caused by TNNI3 variants; they fall mostly in different places as the Primary familial hypertrophic cardiomyopathy variants (7 disease-causing).

Diseases related to Primary familial hypertrophic cardiomyopathy

• Hypertrophic cardiomyopathy, also linked to GLA, JPH2, MYBPC3, MYH6 and 2 more
• Primary dilated cardiomyopathy, also linked to ACTN2, MYBPC3, MYH6, MYH7 and 1 more
• Dilated cardiomyopathy, also linked to JPH2, MYBPC3, MYH7 and TNNI3
• Familial isolated dilated cardiomyopathy, also linked to MYH6, MYH7 and TNNI3
• Left ventricular noncompaction, also linked to MYBPC3 and MYH7
• Primary familial dilated cardiomyopathy, also linked to MYH6 and MYH7
• Restrictive cardiomyopathy, also linked to MYH7 and TNNI3
• Long QT syndrome, also linked to KCNH2
• Fabry disease, also linked to GLA
• Cardiac arrhythmia, also linked to KCNH2
• Short QT syndrome type 3, also linked to KCNH2
• Atrial septal defect, also linked to MYH6

Frequently asked questions

Which genes are linked to Primary familial hypertrophic cardiomyopathy?

In CATVariant, Primary familial hypertrophic cardiomyopathy is linked to 8 analyzed proteins: GLA (Alpha-galactosidase A), MYH7 (Myosin-7), ACTN2 (Alpha-actinin-2), MYBPC3 (Myosin-binding protein C, cardiac-type), JPH2 (Junctophilin-2), TNNI3 (Troponin I, cardiac muscle) and 2 more.

How many genetic variants are linked to Primary familial hypertrophic cardiomyopathy?

579 variants: 14 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 538 are of uncertain significance or have conflicting reports.

Which uncertain variants in Primary familial hypertrophic cardiomyopathy look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Primary familial hypertrophic cardiomyopathy?

Among tools not trained on clinical labels, EVE separates this disease's known disease-causing variants from harmless ones best (AUROC 0.87, based on 11 disease-causing and 36 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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