rs61750625

chr12-5985605-G-Achr12-5985605-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1 PP2 BP4_Strong BS2

The NM_000552.5(VWF):c.6859C>T(p.Arg2287Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,614,122 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9 O:1
• Conservation: PhyloP100: 1.36

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_benign. Variant got -5 ACMG points.

• PM1: In a domain VWFC 1 (size 73) in uniprot entity VWF_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000552.5
• PP2: Missense variant where missense usually causes diseases, VWF
• BP4: Computational evidence support a benign effect (MetaRNN=0.026728868).
• BS2: High AC in GnomAd at 361 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.6859C>T	p.Arg2287Trp	missense_variant	39/52	ENST00000261405.10
VWF	XM_047429501.1	c.6859C>T	p.Arg2287Trp	missense_variant	39/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.6859C>T	p.Arg2287Trp	missense_variant	39/52	1	NM_000552.5	P1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000586 AC: 147 AN: 251052 Hom.: 1 AF XY: 0.000398 AC XY: 54 AN XY: 135696

Gnomad AFR exome AF: 0.00806

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000278 AC: 406 AN: 1461790 Hom.: 3 Cov.: 33 AF XY: 0.000228 AC XY: 166 AN XY: 727190

Gnomad4 AFR exome AF: 0.00980

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.00238 AC: 363 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00238 AC XY: 177 AN XY: 74488

Gnomad4 AFR AF: 0.00823

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000998 Hom.: 0

Bravo AF: 0.00259

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000659 AC: 80

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:6 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 04, 2023	he frequency of this variant in the general population, 0.008 (199/24962 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with Type 1 or Type 2A von Willebrand disease (vWD) (PMID: 16985174 (2007), 23340442 (2013)), but it has also been reported in healthy individuals (PMID: 22197721 (2012), 23216583 (2013)). In in-vivo functional studies, this variant caused mild intracellular retention and impaired secretion of VWF protein (PMID: 16985174 (2007), 19566550 (2009), 23340442 (2013), 31035301 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 19, 2022	PS3 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 01, 2023	The VWF c.6859C>T; p.Arg2287Trp variant (rs61750625) is reported in the literature in individuals affected with von Willebrand disease (Goodeve 2007, Eikenboom 2009, Flood 2013), but has also been found in unaffected controls (Bellissimo 2012). Functional analyses of the variant protein show slightly impaired secretion (Flood 2013). This variant is reported in ClinVar (Variation ID: 100450) and is found in the African population with an allele frequency of 0.8% (199/24962 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.34). Due to limited information, the clinical significance of the p.Arg2287Trp variant is uncertain at this time. References: Bellissimo DB et al. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood. 2012 Mar 1;119(9):2135-40. PMID: 22197721. Eikenboom J et al. Expression of 14 von Willebrand factor mutations identified in patients with type 1 von Willebrand disease from the MCMDM-1VWD study. J Thromb Haemost. 2009 Aug;7(8):1304-12. PMID: 19566550. Flood VH et al. Collagen binding provides a sensitive screen for variant von Willebrand disease. Clin Chem. 2013 Apr;59(4):684-91. PMID: 23340442. Goodeve A et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood. 2007 Jan 1;109(1):112-21. PMID: 16985174. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2023	Identified in multiple individuals with different subtypes of von Willebrand disease, including type 1, type 2M, and type 2A in the published literature, however, many individuals had other variants identified in VWF, and additional clinical or segregation information to support pathogenicity was not provided (Kakela et al., 2006; Goodeve et al., 2007; Flood et al., 2013); Published functional studies demonstrate a damaging effect with mild reduction in the amount of secreted VWF protein (Eikenboom et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19506359, 20981092, 24482836, 18344424, 16985174, 22197721, 22995991, 23216583, 23340442, 23690449, 19566550, 16321553, 33556167, 35552711, 35734101) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 18, 2022

Variant summary: VWF c.6859C>T (p.Arg2287Trp) results in a non-conservative amino acid change located in the VWFC domain (IPR001007) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 251052 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in VWF causing Von Willebrand Disease (0.00059 vs ND), allowing no conclusion about variant significance. c.6859C>T has been reported in the literature in individuals affected with Von Willebrand Disease in settings of normal/inconsistent multimer results and normal/low VWF:CB, who also harbored other variants in the VWF gene (example, Kakela_2006, Goodeve_2007, Flood_2013, Sadler_2021). These report(s) do not provide unequivocal conclusions about a penetrant association of this variant with Von Willebrand Disease. At least one publication reports experimental evidence evaluating an impact on protein function (Eikenboom_2009). The most pronounced variant effect results in a mild-reduction in the levels of secreted VWF with no signs of intracellular retention leading to a categorization as "probably causative". Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 18, 2021

- -

von Willebrand disease type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Oct 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.077
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.76
MPC		0.94
ClinPred		0.083	T
GERP RS		1.6
Varity_R		0.15
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61750625; hg19: chr12-6094771; COSMIC: COSV54616449;