COL6A1

Chr 21ADAR

collagen type VI alpha 1 chain

Also known as: BTHLM1, BTHLM1A, OPLL, UCHMD1, UCHMD1A

NCBI Gene: 1291 ENSG00000142156 UniProt: P12109 OMIM: 120220

The protein encodes the alpha-1 subunit of type VI collagen, which forms heterotrimers that are major structural components of extracellular matrix microfibrils. Mutations cause Bethlem myopathy and Ullrich congenital muscular dystrophy through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves disruption of the collagen VI heterotrimer structure, compromising extracellular matrix integrity in muscle and other tissues.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.232 OMIM phenotypes

Clinical Summary— COL6A1

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Gene-Disease Validity (ClinGen)

collagen 6-related myopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 1.000

Z-score 6.45

OE 0.13 (0.07–0.23)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.50Z-score

OE missense 0.95 (0.89–1.01)

644 obs / 680.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.23)

0≤0.351.4

Missense OE?0.95 (0.89–1.01)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 8 / 63.5Missense obs/exp: 644 / 680.8Syn Z: -1.42

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCOL6A1-related myopathyOTHERAD

This gene — mechanism propensity

0.5576th %ile

GOF

0.6247th %ile

LOF

0.53top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.23

DN1 literature citation

Literature Evidence

DNThus, dimer formation and secretion of abnormal tetramers can occur and exert a strong dominant negative effect on microfibrillar assembly, leading to a loss of normal localization of collagen VI in the basement membrane surrounding muscle fibers.1

LOFReduced collagen VI causes Bethlem myopathy: a heterozygous COL6A1 nonsense mutation results in mRNA decay and functional haploinsufficiency.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References