12-6019297-C-T

Variant names:

• chr12-6019297-C-T
• rs61750072
• NM_000552.5:c.4121G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PS4 PP1_Moderate PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.4121G>A is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 1374. This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor computational predictor REVEL gives a score of 0.879, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Family M proband I.1 (PMID:7734373) with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a complete set of vWF multimers present but relative reduction of the larger multimers, low VWF:RCo/VWF:Ag ratio (<0.4), and VWF:RCo <3-10 IU/dl (PP4). Additional consistent phenotypes included FVIII activity consistent with VWF antigen. This variant has been reported in >8 additional probands with consistent laboratory phenotypes (PS4_VeryStrong; PMIDs: 7620154, 9031470, 11154147, 7734373, 38315875, 28083987, 28536718). The variant has been reported to segregate with VWD type [2A/2M] through at least 2 affected meioses in at least 2 families (PP1_Moderate; PMID:7734373, PMID:7620154). A platelet binding assay in COS-7 cells expressing the recombinant VWF variant showed decreased binding indicating that this variant has a damaging effect on protein function relative to the rVWF wild-type control (PMID:10845912, PS3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2 based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PS4_VeryStrong, PM2_supporting, PP1_Moderate, PP3, PP4.Recent analysis (PMID:38315875) reports that patients with R1374H have severely reduced VWF:GPIbR/VWF:Ag and a modest decrease in VWF:CB/VWF:Ag ratios. This can be explained by 2 defects, (1) a reduced VWF A1 domain binding to GPIb and (2) an altered VWF multimeric pattern in which patients showed a slightly diminished proportion of HMWM and little increase of low and intermediate multimers. They hypothesize that the slight reduction of HMWM (characteristic of type 2A) is primarily responsible for marginally reduced VWF:CB/VWF:Ag ratio, whereas the markedly reduced VWF:GPIbR/VWF:Ag ratio is mainly because of a type 2M defect (diminished binding of A1-GPIb) and propose a subtype designation of 2M/2A for this variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228541/MONDO:0013304/081

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 6.75
• Publications: 30 publications found

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]

VWF Gene-Disease associations (from GenCC):

• hereditary von Willebrand disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• von Willebrand disease 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.4121G>A	p.Arg1374His	missense	Exon 28 of 52	NP_000543.3	P04275-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.4121G>A	p.Arg1374His	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.4121G>A	p.Arg1374His	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+10045G>A		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461642 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	von Willebrand disease type 2 (6)
5	-	-	not provided (6)
2	-	-	Hereditary von Willebrand disease (2)
1	-	-	Prolonged bleeding time;C1458140:Abnormal bleeding (1)
1	-	-	von Willebrand disease type 1 (1)
1	-	-	von Willebrand disease type 1;C1282968:Von Willebrand disease type 2A;C1282974:von Willebrand disease type 2M (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		6.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.81		Gain of catalytic residue at K1371 (P = 0.0023)
MVP		0.93
MPC		1.0
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.69
gMVP		0.84
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61750072; hg19: chr12-6128463; COSMIC: COSV54615184; COSMIC: COSV54615184;