rs61749370

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-6019621-G-A
• chr12-6019621-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP5

This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.3797C>T variant in VWF is a missense variant predicted to cause substitution of proline by leucine at amino acid 1266 (p.Pro1266Leu). The population frequency and in silico pathogenicity predictors of this variant are between the pathogenic and benign thresholds established by the VWD VCEP. This variant has been extensively researched and published in the literature and has been associated with VWD type 2B Malmö/NY. This sub-type of VWD type 2B is characterized by very mild clinical presentation if any, typically no thrombocytopenia and normal multimers. No published case where the variant under consideration was the sole driver of disease had a combination of: activity/antigen ratio <0.7, documented abnormal bleeding phenotype, and enhanced response to ristocetin. This variant has been observed in at least 1 patient with an alternate molecular basis for disease. The patient with VWD type 2, also carried the Arg1315His variant, which has been classified likely pathogenic respectively for VWD type 2M respectively by the VWD VCEP (BP5; PMIDs 16985174). Additionally, carriers of this variant have been documented as being treated with DDAVP without subsequent thrombocytopenia in at least two reports (PMIDs 20305138, 27353798). This observation suggests that the enhanced response to ristocetin data in patients is potentially an artifact and does not represent a biologically relevant increase in binding affinity to GPIb. In summary, this variant meets the criteria to be classified as likely benign for hereditary VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BP5. (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/CA114170/MONDO:0019565/081

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (2 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Likely benign reviewed by expert panel P:20 U:2 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: Likely_benign. The variant received -1 ACMG points.

• BP5: 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>T	p.Pro1266Leu	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>T	p.Pro1266Leu	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.3797C>T	p.Pro1266Leu	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+9721C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000797 AC: 199 AN: 249794 AF XY: 0.000755

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.000392

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000646 AC: 943 AN: 1460608 Hom.: 2 Cov.: 38 AF XY: 0.000656 AC XY: 477 AN XY: 726638

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000179 AC: 6 AN: 33468

American (AMR) AF: 0.00105 AC: 47 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 82 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.000418 AC: 36 AN: 86192

European-Finnish (FIN) AF: 0.00463 AC: 247 AN: 53388

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.000426 AC: 473 AN: 1111052

Other (OTH) AF: 0.000829 AC: 50 AN: 60338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000927 AC XY: 69 AN XY: 74428

African (AFR) AF: 0.000217 AC: 9 AN: 41562

American (AMR) AF: 0.000981 AC: 15 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68022

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

Alfa AF: 0.000700 Hom.: 1

Bravo AF: 0.000842

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000741 AC: 90

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	1	-	not provided (7)
6	-	-	von Willebrand disease type 2 (6)
3	-	1	Hereditary von Willebrand disease (5)
2	-	-	von Willebrand disease type 1 (2)
-	1	-	not specified (1)
1	-	-	Thrombocytopenia (1)
1	-	-	von Willebrand disease type 1;C1264041:von Willebrand disease type 3 (1)
1	-	-	Von Willebrand disease type 2B (1)
1	-	-	VWF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.33
Sift	Benign	0.27	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.58
MVP		0.83
MPC		0.85
ClinPred		0.040	T
GERP RS		5.2
Varity_R		0.27
gMVP		0.84
Mutation Taster		=69/31	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: COSV54611831;