Gene-disease assertions not curated here (add link or write note): Did not curate AR Ullrich congenital muscular dystrophy; Invitae curated as strong in GenCC
GenCC - Strong by both Ambry and Invitae (sufficient to skip clinical validity scoring; however, making notes below as I want to review gene further to document the clinical phenotype.
BabySeq - none
Clinical Validity Scoring Notes and points
Hicks 2014 PMID: 24334769
Two families (1 and 2) with Bethlem myopathy were found to have COL12A1 variants via WES. Family 1 - NM004370; c.G8357A: p.Gly2786Asp segregated in mother (1a) and daughter (proband, 1b). Family 2 NM004370c.C5893T:p.Arg1965Cys segregated in father (2a), and two sons (2b, 2C). Abnormal muscle biopsy in 1b and family 2 per fig 3, and showed dermal intracellular retention of collagen 12, collagen 12 labelling weaker at the fascia in patient 1a and 2a. 1 point each for variants (2 POINTS TOTAL), 3 total segs.
Zou 2014 PMID: 24334604
Family A is a recessive congenital myopathy family
Family B - Hypotonia, proximal joint contractures and distal joint hyperlaxity were noted during the first year of life. NM004370 c. 7167 T>C; NP004361 p. Ile2334Thr identified via candidate gene sequencing following haplotype analysis. immunocytochemical of dermal fibroblasts showed a reduction of collagen XII matrix in culture derived from patient B (Fig3b). Variant was de novo per the text, but I don’t see any evidence that parents were sequenced; however It does seem likely to be de novo based on the descriptions of family A where parents were tested (1.5 point)
Col12a1 -/- mice had decreased grip strength and decreased hindlimb splaying (indicating muscle weakness). Skeletal muscles from null mice showed decrease tetanic and specific force. 0.5 POINT MOUSE MODEL (downgrading since it is an AR model)
Punetha 2017 PMID: 27348394
COL12A1 c.8329G>C (p.Gly2777Arg) identified via targeted sequencing panel in a patient with profound hypotonia, joint laxity at birth, and a pregnancy complicated by oligohydramnios and intrauterine growth retardation. Patient fibroblast studies confirmed intracellular retention of the COL12A1 protein consistent w/ a dominant negative mutation. Absent in proband’s mother (father unavailable). 1 POINT
Coppens 2022 PMID: 35019233
Patient w/ fetal hypokinesia, severe neonatal weakness, hyperlaxity, high arched palate, retrognathia, club feet, pectus excavatum. Motor dleayed, muscle strength improved over time but hyperlaxity was very severe with recurrent joint dislocations. Trio exome identified in frame del exons 45-54 in COL12A1. 1.5 point.
Source:
Clinical ValidityPoints Total
Source:
Clinical ValidityClassification
Definitive (12pts)
Strong (12pts)
Moderate (7-11pts)
Limited (0.1-6pts)
No genetic evidence
Refuted
Disputed
Source:
MolecularMechanism
Loss of function
Gain of function
Dominant negative
Unknown
Other
unknown (proposed dominant negative in PMID: 27348394)
Dysmorphic features (facial asymmetry with skull flattening, micrognathia, short nose, big dysplastic ears, high-arched palate, pectus excavatum and long slender fingers)
Delayed motor milestones.
Poor weight gain.
PMID: 35019233
Patient w/ fetal hypokinesia, severe neonatal weakness, hyperlaxity, high arched palate, retrognathia, club feet, pectus excavatum. Motor dleayed, muscle strength improved over time but hyperlaxity was very severe with recurrent joint dislocations.
LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant
Curation Summary
The COL12A1 gene is associated with autosomal dominant Bethlem myopathy, which is characterized by neonatal or infantile hypotonia, joint laxity, hip dyslocation, flexion finger contractures, delayed motor milestones, proximal weakness, scapular winging, and facial features such as micrognathia, short nose, dysplastic ears, and high arched alate. The onset is typically from birth or in childhood, and muscle strength tends to improve during teenage years (PMID: 24334769, 24334604, 27348394, 35019233). This gene is also associated with autosomal recessive Ullrich congenital muscular dystrophy, a severe autosomal recessive disorder characterized by joint hypermobility, proximal contractures, and muscle weakness precluding ambulation (PMID: 24334604).