Myofibrillar myopathy: genes and variants

Genes linked to Myofibrillar myopathy

• FLNC: Filamin-C

  It crosslinks actin and anchors signaling and structural proteins at Z-discs, costameres, and other mechanically stressed sites in striated muscle. Pathogenic variants can cause arrhythmogenic or dilated cardiomyopathy as well as myofibrillar and distal myopathies.

  7 disease-causing and 1,710 uncertain variants in FLNC are linked to Myofibrillar myopathy.

• BAG3: BAG family molecular chaperone regulator 3

  It coordinates chaperone-assisted protein quality control and autophagy, particularly in mechanically stressed cardiac and skeletal muscle. Pathogenic variants can impair sarcomere maintenance and cause dilated cardiomyopathy or myofibrillar myopathy.

  5 disease-causing and 527 uncertain variants in BAG3 are linked to Myofibrillar myopathy.

• LDB3: LIM domain-binding protein 3

  It organizes Z-disc protein complexes and helps maintain sarcomere integrity during repeated muscle contraction. Pathogenic variants can cause myofibrillar myopathy and dilated or other forms of cardiomyopathy.

  1 disease-causing and 456 uncertain variants in LDB3 are linked to Myofibrillar myopathy.

• DES: Desmin

  Its desmin filaments mechanically integrate sarcomeres with the nucleus, mitochondria, and cell junctions in striated muscle. Pathogenic variants cause desmin-related myopathy and can produce cardiomyopathy, conduction disease, and skeletal-muscle weakness.

  0 disease-causing and 0 uncertain variants in DES are linked to Myofibrillar myopathy.

Known disease-causing variants in Myofibrillar myopathy

Which prediction tools work for Myofibrillar myopathy

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

• PolyPhen-2: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 83 out of 100
• SIFT: 82 out of 100
• MetaLR: 70 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Hypertrophic cardiomyopathy is also caused by FLNC variants; they fall mostly in different places as the Myofibrillar myopathy variants (10 disease-causing).
• Distal myopathy with posterior leg and anterior hand involvement is also caused by FLNC variants; they fall mostly in different places as the Myofibrillar myopathy variants (9 disease-causing).
• Restrictive cardiomyopathy is also caused by FLNC variants; they fall mostly in different places as the Myofibrillar myopathy variants (3 disease-causing).
• Dilated cardiomyopathy is also caused by LDB3 variants; they fall mostly in different places as the Myofibrillar myopathy variants (4 disease-causing).

Diseases related to Myofibrillar myopathy

• Dilated cardiomyopathy, also linked to BAG3, DES, FLNC and LDB3
• Hypertrophic cardiomyopathy, also linked to BAG3, FLNC and LDB3
• Primary familial dilated cardiomyopathy, also linked to DES and LDB3
• Familial isolated dilated cardiomyopathy, also linked to BAG3 and DES
• Primary dilated cardiomyopathy, also linked to DES
• Desmin-related myofibrillar myopathy, also linked to DES
• Left ventricular noncompaction, also linked to LDB3
• Distal myopathy with posterior leg and anterior hand involvement, also linked to FLNC
• Restrictive cardiomyopathy, also linked to FLNC
• Myopathy, also linked to FLNC
• Arrhythmogenic right ventricular cardiomyopathy, also linked to DES
• Dilated cardiomyopathy 1HH, also linked to BAG3

Frequently asked questions

Which genes are linked to Myofibrillar myopathy?

In CATVariant, Myofibrillar myopathy is linked to 4 analyzed proteins: FLNC (Filamin-C), BAG3 (BAG family molecular chaperone regulator 3), LDB3 (LIM domain-binding protein 3) and DES (Desmin).

How many genetic variants are linked to Myofibrillar myopathy?

2,958 variants: 13 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 2,693 are of uncertain significance or have conflicting reports.

Which uncertain variants in Myofibrillar myopathy 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 Myofibrillar myopathy?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.83, based on 10 disease-causing and 12 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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