rs1800382

Variant names:

• chr12-6019222-C-T
• rs1800382
• NM_000552.5:c.4196G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-6019222-C-T
• chr12-6019222-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 7P and 5B. BP5 BS1 PM5_Supporting PP3 PP4 PS3

This summary comes from the ClinGen Evidence Repository: The NM_000552.5:c.4196G>A variant in VWF is a missense variant predicted to cause substitution of arginine by histidine at amino acid 1399. The Arg1399His variant has a relatively high Grpmax filtering allele frequency in gnomAD v4.1 of 0.01289 (based on 15410/1179858 alleles in the European non-Finnish population), which is higher than the ClinGen VWD VCEP threshold (>0.01; BS1). At least 4 patients with this variant displayed excessive mucocutaneous bleeding as well as the laboratory phenotype of an abnormal collagen binding assay, which together are consistent with VWD Type 2M (PP4, PS4_Moderate), however, all patients exhibited a VWF:RCo/VWF:Ag ratio between 0.7 and 1.5 (PMID:22507569, PMID:28083987, PMID:28971901). This variant has also been observed in at least 2 patients with an alternate molecular basis for disease, one of whom exhibited VWD Type 2B phenotypes and harbored the c.3916C>T (p.Arg1306Trp) variant in cis (PMID:1672694), which is classified as pathogenic for VWD Type 2B by the ClinGen VWD VCEP. The second patient exhibited a VWD Type 2M phenotype and harbored this variant as well as the c.4225G>T (p.Val1409Phe) variant, which is classified as likely pathogenic for VWD Type 2M by the ClinGen VWD VCEP (PMID:28971901). The computational predictor REVEL gives a score of 0.698, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Another missense variant in the same codon, NM_000552.5(VWF):c.4195C>T (p.Arg1399Cys), has been reported in multiple patients with VWD Type 2M (PMID:17000885, PMID:26988807, PMID:28083987). This variant has been classified as likely pathogenic by the ClinGen VWD VCEP (PM5_supporting). Multiple functional studies show a deleterious effect on protein function, including a hydrodynamic mouse model showing >75% loss of both collagen 4 binding and platelet adhesion PMID:25662333) and a knock-in mouse model showing decreased VWF binding to collagen IV but not collagen III, decreased platelet adhesion, and increased bleeding, indicating a hypomorphic effect (PMID:30565388). Exogenous expression of the p.Arg1399His mutant in 293 cells identified undetectable binding to type VI (PMID:22507569) and type IV collagen (PMID:25662333) (PS3). In summary, this variant meets the criteria to be classified as a Variant of Unknown Significance for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3, PM5_supporting, PP3, PP4, BP5, BS1. (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/13/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA114133/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.0088 (11 hom., cov: 31)
  • Exomes 𝑓: 0.011 (147 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:10 B:4
• Conservation: PhyloP100: 2.26
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PS3: 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.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.4196G>A	p.Arg1399His	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.4196G>A	p.Arg1399His	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.4196G>A	p.Arg1399His	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+10120G>A		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.00877 AC: 1334 AN: 152120 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00858 AC: 2152 AN: 250796 AF XY: 0.00921

Gnomad AFR exome AF: 0.00243

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.00784

GnomAD4 exome AF: 0.0114 AC: 16651 AN: 1461652 Hom.: 147 Cov.: 98 AF XY: 0.0112 AC XY: 8149 AN XY: 727138

African (AFR) AF: 0.00197 AC: 66 AN: 33472

American (AMR) AF: 0.00347 AC: 155 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 413 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00366 AC: 316 AN: 86250

European-Finnish (FIN) AF: 0.0126 AC: 673 AN: 53402

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5762

European-Non Finnish (NFE) AF: 0.0130 AC: 14451 AN: 1111840

Other (OTH) AF: 0.00936 AC: 565 AN: 60378

GnomAD4 genome AF: 0.00876 AC: 1334 AN: 152238 Hom.: 11 Cov.: 31 AF XY: 0.00875 AC XY: 651 AN XY: 74426

African (AFR) AF: 0.00193 AC: 80 AN: 41534

American (AMR) AF: 0.00360 AC: 55 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4818

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0141 AC: 959 AN: 68018

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.0118 Hom.: 5

Bravo AF: 0.00740

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0141 AC: 121

ExAC AF: 0.00866 AC: 1051

EpiCase AF: 0.0114

EpiControl AF: 0.0101

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (6)
1	1	-	Hereditary von Willebrand disease (2)
-	1	1	von Willebrand disease type 1 (2)
-	1	1	von Willebrand disease type 2 (2)
1	-	-	Abnormality of coagulation (1)
-	1	-	not specified (1)
-	1	-	von Willebrand disease type 1;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	-0.13	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.70
Sift	Benign	0.031	D
Sift4G	Uncertain	0.024	D
Polyphen		0.98	D
Vest4		0.58
MVP		0.78
MPC		0.99
ClinPred		0.012	T
GERP RS		4.0
Varity_R		0.22
gMVP		0.78
Mutation Taster		=81/19	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: rs1800382; hg19: chr12-6128388; COSMIC: COSV99075167; COSMIC: COSV99075167;