12-6019621-G-T

Variant names:

• chr12-6019621-G-T
• rs61749370
• NM_000552.5:c.3797C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP4

This summary comes from the ClinGen Evidence Repository: The NM_000552.5:c.3797C>A variant in VWF is a missense variant predicted to cause substitution of proline by glutamine at amino acid 1266. Population and in silico predictors were between the pathogenic and benign thresholds for the respective codes. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio and no loss of HMW multimers (described as non-selective loss and low intensity but high molecular weight bands are still present), which is specific for VWD type 2M (PP4, PMID 23179108).The majority of reported cases were asserted as VWD type 2M but there were also assertions for type 2B and type 1. No reported case in the literature had a combination of activity/antigen ratio <0.7, documented abnormal bleeding phenotype, and enhanced platelet binding. There is conflicting evidence of altered platelet binding phenotype evidenced by in vitro assays showing both enhanced GPIb and decreased GPIb binding (PMIDs 23179108, 30488424). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant VWD type 2 based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0; May 6th, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA228441/MONDO:0013304/081

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (3 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:9 U:6 B:1 O:2
• Conservation: PhyloP100: 3.40
• Publications: 52 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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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.3797C>A	p.Pro1266Gln	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.3797C>A	p.Pro1266Gln	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.3797C>A	p.Pro1266Gln	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+9721C>A		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000977

Gnomad SAS AF: 0.00561

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000276 AC: 69 AN: 249794 AF XY: 0.000348

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000543 AC: 793 AN: 1460696 Hom.: 3 Cov.: 38 AF XY: 0.000674 AC XY: 490 AN XY: 726690

African (AFR) AF: 0.000120 AC: 4 AN: 33468

American (AMR) AF: 0.000492 AC: 22 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000128 AC: 5 AN: 39048

South Asian (SAS) AF: 0.00376 AC: 324 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5760

European-Non Finnish (NFE) AF: 0.000343 AC: 381 AN: 1111636

Other (OTH) AF: 0.000796 AC: 48 AN: 60328

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74412

African (AFR) AF: 0.000168 AC: 7 AN: 41562

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000979 AC: 5 AN: 5106

South Asian (SAS) AF: 0.00561 AC: 27 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000291 Hom.: 1

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000453 AC: 55

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	3	-	not provided (6)
2	1	-	von Willebrand disease type 2 (3)
2	-	-	Hereditary von Willebrand disease (3)
1	1	-	von Willebrand disease type 1 (2)
-	-	1	EBV-positive nodal T- and NK-cell lymphoma (1)
-	1	-	not specified (1)
1	-	-	von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 (1)
1	-	-	VWF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.85
MPC		0.84
ClinPred		0.13	T
GERP RS		5.2
Varity_R		0.28
gMVP		0.87
Mutation Taster		=68/32	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: rs61749370; hg19: chr12-6128787; COSMIC: COSV54610558;