rs61749393

Positions:

• chr12-6019478-C-A
• chr12-6019478-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3 PP4 PM2_Supporting PS2_Moderate PM5 PS3

This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.3940G>T (p.Val1314Phe) missense variant has been reported in at least 1 proband with prolonged bleeding time (>20 minutes), decreased binding capacity to GPIb, vWFAg (25 U/dL) associated with the absence of vWFRCo (<5 U/dL) for a ratio of <0.2, and an absence of high molecular weight and intermediate multimers in the plasma. Additional features included decreased levels of VIIIC (30 U/dL) and a total lack of ristocetin platelet aggregation (RIPA) at concentrations of modulator between 0 and 2 mg/mL. His platelet count is around 120 × 10^9/L and decreases to approximately 50 × 10^9/L at the time of bleeding episodes (PP4; PMID:8298143). As reported by the authors, there is a discrepancy in this patient between an apparent type 2A phenotype and 2B genotype. This discrepancy can be explained as an extremely severe form of type-IIB vWD, where the variant strongly increases the affinity of vWF for platelet GPIb, which might result in plasma in a spontaneous binding of both HMW and intermediate-sized multimers to the platelets. This could explain the thrombocytopenia of the propositus and the clearance of the large and intermediate forms of vWF from the patient’s plasma. The variant was identified as a de novo occurrence in this patient (PS2_moderate; PMIDs: 1419803). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.741, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3).A GP1b binding assay performed with the recombinant Val1314Phe mutant vWF expressed by COS-7 cells showed spontaneous binding at low doses of ristocetin (PMID:8298143 and PMID:8630394), and enhanced binding to platelets in the presence of low-dose ristocetin compared with WT (PMID:8630394), indicating that this variant has a gain of function effect on the protein (PS3_supporting). Another type 2B variants have been reported at this amino acid residue; Val1314Leu and classified pathogenic by the VWD VCEP (PM5). In summary, the variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2B based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PS2_moderate, PP3, PP4, PM5, and PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228498/MONDO:0015629/081

• Frequency: Genomes: not found (cov: 32)
• Consequence: VWF ENST00000261405.10 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:1 O:1
• Conservation: PhyloP100: 4.20

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.3940G>T	p.Val1314Phe	missense_variant	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3940G>T	p.Val1314Phe	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3940G>T	p.Val1314Phe	missense_variant	28/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.421-25544G>T		intron_variant, non_coding_transcript_variant		4
VWF	ENST00000539641.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 11, 2017	- -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.77	D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.84	P
Vest4		0.79
MutPred		0.85		Gain of sheet (P = 0.0344);
MVP		0.89
MPC		0.41
ClinPred		0.69	D
GERP RS		3.8
Varity_R		0.52
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61749393; hg19: chr12-6128644;