Bethlem myopathy: genes and variants

Genes linked to Bethlem myopathy

• COL6A2: Collagen alpha-2(VI) chain

  It assembles with other collagen VI chains into extracellular microfibrils that support muscle and connective-tissue integrity. Dominant or recessive pathogenic variants cause collagen VI-related muscular dystrophy and myopathy across a broad severity spectrum.

  39 disease-causing and 635 uncertain variants in COL6A2 are linked to Bethlem myopathy.

• COL6A1: Collagen alpha-1(VI) chain

  It contributes to extracellular microfibrils that connect cells with surrounding matrix and are especially important in skeletal muscle and connective tissue. Pathogenic variants can cause collagen VI-related myopathies ranging from Bethlem muscular dystrophy to severe Ullrich congenital muscular dystrophy.

  36 disease-causing and 441 uncertain variants in COL6A1 are linked to Bethlem myopathy.

• COL6A3: Collagen alpha-3(VI) chain

  It forms part of collagen VI microfibrils that organize the extracellular matrix around muscle fibers and many other cells. Pathogenic variants can cause Bethlem or Ullrich-spectrum collagen VI myopathy and, in some alleles, isolated dystonia.

  21 disease-causing and 1,424 uncertain variants in COL6A3 are linked to Bethlem myopathy.

• LMNA: Prelamin-A/C

  The gene product produces lamins A and C, structural proteins that form the nuclear lamina beneath the inner nuclear membrane. Lamins help maintain nuclear shape and organize chromatin, and LMNA variants are associated with muscular dystrophy, cardiomyopathy, lipodystrophy, and premature-aging syndromes.

  1 disease-causing and 0 uncertain variants in LMNA are linked to Bethlem myopathy.

Where Bethlem myopathy variants cluster

• COL6A1 Triple-helical region (positions 257–592): 36 of 36 disease-causing changes, 3.1× more than its size predicts.
• COL6A3 Collagen-like 1 (positions 2038–2097): 13 of 21 disease-causing changes, 32.8× more than its size predicts.
• COL6A2 Triple-helical region (positions 257–590): 31 of 39 disease-causing changes, 2.4× more than its size predicts.
• COL6A3 VWFA 9 (positions 1639–1812): 3 of 21 disease-causing changes, 2.6× more than its size predicts.

Known disease-causing variants in Bethlem myopathy

Showing 60 of 97.

Uncertain variants in Bethlem myopathy that look disease-causing

Which prediction tools work for Bethlem myopathy

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

• CATVariant: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 95 out of 100
• CADD: 93 out of 100
• SIFT: 90 out of 100
• phyloP: 87 out of 100
• EVE: 86 out of 100

Same protein, different disease

• Ullrich congenital muscular dystrophy is also caused by COL6A2 variants; they fall partly in the same places as the Bethlem myopathy variants (8 disease-causing).
• Charcot-Marie-Tooth disease is also caused by LMNA variants; they fall mostly in different places as the Bethlem myopathy variants (130 disease-causing).
• Dilated cardiomyopathy is also caused by LMNA variants; they fall mostly in different places as the Bethlem myopathy variants (21 disease-causing).
• Familial partial lipodystrophy, Dunnigan type is also caused by LMNA variants; they fall mostly in different places as the Bethlem myopathy variants (13 disease-causing).
• Emery-Dreifuss muscular dystrophy is also caused by LMNA variants; they fall mostly in different places as the Bethlem myopathy variants (12 disease-causing).
• Congenital muscular dystrophy due to LMNA mutation is also caused by LMNA variants; they fall mostly in different places as the Bethlem myopathy variants (11 disease-causing).

Diseases related to Bethlem myopathy

• Ullrich congenital muscular dystrophy, also linked to COL6A1, COL6A2 and COL6A3
• Collagen 6-related myopathy, also linked to COL6A1, COL6A2 and COL6A3
• Muscular dystrophy, also linked to COL6A2 and LMNA
• Charcot-Marie-Tooth disease, also linked to LMNA
• Dilated cardiomyopathy, also linked to LMNA
• Primary dilated cardiomyopathy, also linked to LMNA
• Arrhythmogenic right ventricular dysplasia, also linked to LMNA
• Familial partial lipodystrophy, Dunnigan type, also linked to LMNA
• Emery-Dreifuss muscular dystrophy, also linked to LMNA
• Fetal anomalies with a likely genetic cause, also linked to COL6A3
• Congenital muscular dystrophy due to LMNA mutation, also linked to LMNA
• Primary familial dilated cardiomyopathy, also linked to LMNA

Frequently asked questions

Which genes are linked to Bethlem myopathy?

In CATVariant, Bethlem myopathy is linked to 4 analyzed proteins: COL6A2 (Collagen alpha-2(VI) chain), COL6A1 (Collagen alpha-1(VI) chain), COL6A3 (Collagen alpha-3(VI) chain) and LMNA (Prelamin-A/C).

How many genetic variants are linked to Bethlem myopathy?

2,986 variants: 97 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 2,500 are of uncertain significance or have conflicting reports.

Which uncertain variants in Bethlem myopathy look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example COL6A1 G287E. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Bethlem myopathy?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 83 disease-causing and 20 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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