rs61749385

Positions:

• chr12-6019501-C-A
• chr12-6019501-C-G
• chr12-6019501-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000552.5(VWF):​c.3917G>T​(p.Arg1306Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1306Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.22

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a disulfide_bond (size 186) in uniprot entity VWF_HUMAN there are 58 pathogenic changes around while only 4 benign (94%) in NM_000552.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6019501-C-T is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VWF. . Gene score misZ 0.98969 (greater than the threshold 3.09). Trascript score misZ 3.5064 (greater than threshold 3.09). GenCC has associacion of gene with von Willebrand disease type 2M, hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease type 2N, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease 3, von Willebrand disease 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 12-6019501-C-A is Pathogenic according to our data. Variant chr12-6019501-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 100301.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-6019501-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.3917G>T	p.Arg1306Leu	missense_variant	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3917G>T	p.Arg1306Leu	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3917G>T	p.Arg1306Leu	missense_variant	28/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.421-25567G>T		intron_variant, non_coding_transcript_variant		4
VWF	ENST00000539641.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461650 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

von Willebrand disease type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Apr 26, 2022

- -

Hereditary von Willebrand disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 15, 2023

Variant summary: VWF c.3917G>T (p.Arg1306Leu) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251092 control chromosomes. c.3917G>T has been reported in the literature in individuals affected with Von Willebrand Disease (e.g. Facey_1999, Caron_2006). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant showed a similar multimer composition but exhibited binding to fixed platelets both in the presence and absence of ristocetin (Facey_1999). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. In addition, other variants involving codon R1306 (p.R1306Q, p.R1306P, p.R1306W) have been reported to associate with Von Willebrand disease (HGMD, ClinVar). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Other:1

not provided, no classification provided

literature only

Academic Unit of Haematology, University of Sheffield

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	0.88	D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.94	P
Vest4		0.85
MutPred		0.82		Loss of MoRF binding (P = 0.0357);
MVP		0.86
MPC		1.0
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.62
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs61749385; hg19: chr12-6128667;