chr12-6021960-C-T

Position:

• chr12-6021960-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The ENST00000261405.10(VWF):​c.3614G>A​(p.Arg1205His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1205C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VWF ENST00000261405.10 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:2
• Conservation: PhyloP100: 2.16

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 15 ACMG points.

• PM1: In a strand (size 3) in uniprot entity VWF_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in ENST00000261405.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6021961-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP5: Variant 12-6021960-C-T is Pathogenic according to our data. Variant chr12-6021960-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6021960-C-T is described in Lovd as [Likely_pathogenic]. Variant chr12-6021960-C-T is described in Lovd as [Pathogenic]. Variant chr12-6021960-C-T is described in Lovd as [Likely_pathogenic]. Variant chr12-6021960-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.3614G>A	p.Arg1205His	missense_variant	27/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3614G>A	p.Arg1205His	missense_variant	27/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3614G>A	p.Arg1205His	missense_variant	27/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.421-28026G>A		intron_variant, non_coding_transcript_variant		4
VWF	ENST00000539641.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 4 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

von Willebrand disease type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4+PM6+PP4+PP1_Moderate -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2006	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Hematology, Radboud University Medical Center	Sep 07, 2021	- -

Hereditary von Willebrand disease Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2023	Variant summary: VWF c.3614G>A (p.Arg1205His) results in a non-conservative amino acid change located in the von Willebrand factor, VWA N-terminal domain (IPR032361) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251494 control chromosomes (gnomAD). c.3614G>A has been reported in the literature in multiple individuals affected with Von Willebrand Disease (example: Bowyer_2018 and Robertson_2011). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30349898, 21711445). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 17, 2023	In the published literature, this variant has been reported in multiple families with type 1 von Willebrand disease (VWD) (PMID: 11756169 (2002), 16870550 (2006), 17080221 (2006), 17190853 (2007), 33556167 (2021). This variant has also been reported to arise de novo (PMID: 16925796 (2006)). Functional studies report this variant results in increased clearance compared to wildtype VWF (PMID: 14613933 (2004), 16889557 (2006), 21346256 (2011)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org).Based on the available information, this variant is classified as pathogenic. -

Reduced quantity of Von Willebrand factor;C4024701:Reduced von Willebrand factor activity Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

VWF-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2023

The VWF c.3614G>A variant is predicted to result in the amino acid substitution p.Arg1205His. This variant has been reported to be causative for VWD type 2M Vicenza and Type 1 in the de novo or heterozygous states in several patients (Schneppenheim et al. 2000. PubMed ID: 10669167; Goodeve et al. 2007. PubMed ID: 16985174; Ahmad et al. 2014. PubMed ID: 24712919; Veyradier et al. 2016. PubMed ID: 26986123). Functional studies of the p.Arg1205His substitution suggest disease is caused by accelerated VWF clearance and reduction in VWF antigen (Pruss et al. 2011. PubMed ID: 21346256). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

von Willebrand factor Vicenza Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.23
Sift	Benign	0.075	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.27	B
Vest4		0.64
MutPred		0.56		Gain of catalytic residue at F1206 (P = 0.001);
MVP		0.63
MPC		0.92
ClinPred		0.92	D
GERP RS		3.9
Varity_R		0.11
gMVP		0.65

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: rs121964895; hg19: chr12-6131126; COSMIC: COSV99780817; COSMIC: COSV99780817;