Hereditary neuropathy or pain disorder

Gene: COL6A3

Green List (high evidence)

COL6A3 is associated with Bethlem myopathy 1C, OMIM #620726; Dystonia 27, OMIM #616411; Ullrich congenital muscular dystrophy 1C, OMIM #620728.

As reviewed by Alexander Rossor, Villar-Quiles et al., 2026 (PMID 620728) described Thirty-seven affected individuals from 32 families harbouring biallelic COL6A3 variants. All carried the recurrent c.7447A>G p.(Lys2483Glu) allele either in homozygosity (24 patients) or compound heterozygosity with a second (often truncating) COL6A3 variant (13 patients). Phase was confirmed in 28 cases. Genetic testing was performed via whole-exome sequencing (WES) or whole-genome sequencing (WGS) in 30 patients, and next-generation sequencing (NGS)-based myopathy panel in 7.

The cohort demonstrated a consistent distal motor neuropathy-like/neuromyopathic phenotype with neurogenic electrophysiological findings. Most patients presented in the first decade of life with an abnormal gait and frequent falls (54%), delayed motor milestones (32%) and foot deformities (19%). Predominant distal weakness was present in 46% of patients. Muscle biopsy (n=12) demonstrated features suggestive of neuropathic involvement in 4 (33%) and mixed neuropathic-myopathic features in 5 (42%). >70% of the patients showed motor conduction abnormalities, and needle EMG (n=31) revealed chronic neurogenic-like features in 84% and mixed neuromyogenic features in 13%.

All patients carried the recurrent c.7447A>G p.(Lys2483Glu) variant and, therefore, despite the presence of a minority of compound heterozygous patients, it remains unclear whether the observed neuropathy-like phenotype represents a variant-specific effect.

In summary, this study provides strong evidence that distal motor neuropathy and neuromyopathy are part of the COL6A3 phenotypic spectrum. A green rating is therefore recommended for the Hereditary neuropathy or pain disorder panel.

Created: 20 Aug 2026, 6:08 p.m. | Last Modified: 20 Aug 2026, 6:08 p.m.

Panel Version: 8.31

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Motor peripheral neuropathy, MONDO:0002316

Publications

• 42520849

Green List (high evidence)

Case series of 35 patients showing evidence of both a peripheral motor neuropathy and myopathy
Sources: Expert list

Created: 16 Aug 2026, 9:29 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
motor neuropathy; myopathy

Publications

• 42520849

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments