Disease: Myopathic Ehlers-Danlos Syndrome (mEDS)
Patient(s): 47 yo male, japanese descent
Variant: COL12A1 NM_004370.6: c.395-1G>A
(Homozygous variant, at splice acceptor site in exon 6, causes in-frame skipping)(located in the genomic region encoding the first von Willebrand factor A domain)
Family: consanguineous parents with no related features of mEDS, healthy older brother
Phenotypes (Childhood): hypotonia, weak spontaneous movements, scoliosis, torticollis, soft plams, undescended testes, motor developmental delay, slender build, triangular face, short palpebral fissures, small nose, small mouth, large ears, bilateral knee dislocations, short stature.
Phenotypes (Adulthood): short stature, high palate, hypermobile small joints, deformed cervical spine, brachycephaly, bilateral long deformed 5th finger, severe scoliosis post surgical fixation, asymmetric pelvis
Classification: sequencing panel found the variant and it was confirmed through sanger sequencing.
According to ClinGenSVI recommendation: PVS1_Strong
Applicable criteria:
1) the one at a GT-AG 1,2 splice site
2) the one exerting exon skipping or use of a crypic splice site that preserved the reading frame.
3) the one at a truncated/altered region critical to protein function; was classified as PM3_Supporting (homozygous)
Variant not registered in gnomAD (PM2_Supporting)
Partial defect of first vWA in collagen XII judged as PS3