Submissions for variant NM_000552.5(VWF):c.3467C>T (p.Thr1156Met)

dbSNP: rs267607328

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851957	SCV000899380	likely pathogenic	Hereditary von Willebrand disease	2019-02-01	criteria provided, single submitter	research
Laboratory of Hematology, Radboud University Medical Center	RCV002264645	SCV002546280	pathogenic	von Willebrand disease type 1	2021-08-19	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000086659	SCV004221513	pathogenic	not provided	2023-04-21	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with von Willebrand Disease (vWD) Type 1 (PMIDs: 11529461 (2001) and 12353070 (2002)), as well as in individuals suspected of vWD (PMIDs: 31064749 (2019) and 33556167 (2021)). In-vitro and in-vivo functional studies have demonstrated that this variant results in a deleterious effect on VWF protein function (PMIDs: 12353070 (2002) and 27533707 (2016)). This variant segregated with disease in a Spanish family with 7 affected individuals with vWD Type 1 (PMID: 11529461 (2001)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586549	SCV005076800	pathogenic	von Willebrand disorder	2024-04-09	criteria provided, single submitter	clinical testing	Variant summary: VWF c.3467C>T (p.Thr1156Met) results in a non-conservative amino acid change located in the Trypsin Inhibitor-like, cysteine rich domain (IPR002919) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 54434 control chromosomes. c.3467C>T has been reported in the literature in multiple individuals from a family affected with Von Willebrand Disease, segregating with disease (example, Casana_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired secretion, increased intracellular retention, loss of high molecular weight multimers and decreased FVIII binding, when compared to WT VWF (White-Adams_2016). The following publications have been ascertained in the context of this evaluation (PMID: 11529461, 16102036, 27533707). ClinVar contains an entry for this variant (Variation ID: 100264). Based on the evidence outlined above, the variant was classified as pathogenic.
Academic Unit of Haematology, University of Sheffield	RCV000086659	SCV000118863	not provided	not provided		no assertion provided	not provided
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV001787053	SCV001572681	likely pathogenic	von Willebrand disease type 3	2020-11-01	no assertion criteria provided	clinical testing	ClinGen Pathogenicity Calculator