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

Disease: Von-willebrand Disorder

Patient: 21 yo, female, Italian descent

Variant: VWF NM_000552.5 c:C3379 > T p.(P1127S), homozygous

Heterozygous and Homozygous polymorphic variant in exon 25

Phenotypes: Bleeding Score System (BSS) = 3 minor bruising normal menstrual bleeding

Family: (father paternity confirmed) Father suffered from rectorrhagia for rectal polyps Mother (same variant, heterozygous) has heavy menstrual bleeding, epistaxis events up to age 30, BBS= 2

Present in dbSNP (rs139579968) MAF in European pop = 0.0001-0.0004

Present in gnomAD, said to be present in 2 transcripts in VWF 40 alleles are present

Predictions: listed with PolyPhen-2 and SIFT = probably damaging to protein expression/function

CADD (score =33) and REVEL(score = 0.748) suggest deleterious effect of pathogenic variant

I-TASSER showed large difference in 3D configuration of sequences differing by a single amino acid.

http://gnomad.broadinstitute.org/variant/1-222736579-C-T Total: 7/245186, 0 homozygotes; MAF = 0.00002855

http://gnomad.broadinstitute.org/variant/1-222757510-A-G Total: 9/273566, 0 homozygotes; MAF = 0.00003290