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