chr12-6044322-C-A

Variant names:

• chr12-6044322-C-A
• rs62643630
• NM_000552.5:c.2411G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PM2_Supporting PS3 PM3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.2411G>T (p.Cys804Phe) missense variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.935, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Factor VIII binding assay performed with the C804F recombinant mutant showed severely impaired binding indicating that this variant has a damaging effect on protein function (PMID:15461624; PS3). At least 1 patient (Patient B) with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity (20 IU/dl) and dramatically decreased VWF:FVIII binding, which is highly specific for VWD type 2N. (PP4_moderate, PMID:15213842). Patient B (PMID:15461624) is compound heterozygous for R854Q (classified Pathogenic by the VWD VCEP; PM3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP3, PM3_supporting, PP4_moderate, PS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114168/MONDO:0015631/090

• Frequency: Genomes: not found (cov: 32)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 7.17

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 Likely_pathogenic. Variant got 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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 rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.2411G>T	p.Cys804Phe	missense_variant	Exon 18 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.2411G>T	p.Cys804Phe	missense_variant	Exon 18 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.2411G>T	p.Cys804Phe	missense_variant	Exon 18 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-50388G>T		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

von Willebrand disease type 2N Pathogenic:2

Feb 04, 2025

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000552.5(VWF):c.2411G>T (p.Cys804Phe) missense variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.935, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Factor VIII binding assay performed with the C804F recombinant mutant showed severely impaired binding indicating that this variant has a damaging effect on protein function (PMID: 15461624; PS3). At least 1 patient (Patient B) with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity (20 IU/dl) and dramatically decreased VWF:FVIII binding, which is highly specific for VWD type 2N. (PP4_moderate, PMID:15213842). Patient B (PMID: 15461624) is compound heterozygous for R854Q (classified Pathogenic by the VWD VCEP; PM3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP3, PM3_supporting, PP4_moderate, PS3. -

Oct 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Other:1

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Academic Unit of Haematology, University of Sheffield

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.84		Gain of catalytic residue at S801 (P = 0);
MVP		0.90
MPC		0.93
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.98
gMVP		0.98

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: rs62643630; hg19: chr12-6153488;