chr12-6019180-G-T

Variant names:

• chr12-6019180-G-T
• rs61750079
• NM_000552.5:c.4238C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000552.5(VWF):​c.4238C>A​(p.Pro1413Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1413L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.23
• Publications: 5 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 type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000552.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease 1, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease type 2M, von Willebrand disease 3, von Willebrand disease type 2N.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.4238C>A	p.Pro1413Gln	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.4238C>A	p.Pro1413Gln	missense_variant	Exon 28 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.4238C>A	p.Pro1413Gln	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-25246C>A		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 99

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

May 21, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VWF c.4238C>A; p.Pro1413Gln variant (rs61750079), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 439337). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 1413 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Other amino acid substitutions at this codon (p.Pro1413Leu, p.Pro1413Arg) have been reported in individuals with von WIllebrand disease; however, they have not been demonstrated to be disease-causing (Berber 2017, Goodeve 2007, James 2007, Veyradier 2016). In addition, computational analyses (Alamut v.2.11) predict that the p.Pro1413Gln variant may impact splicing by creating a novel cryptic splice site, although RNA analyses would be required to confirm this. Given the lack of clinical and functional data, the significance of the p.Pro1413Gln variant is uncertain at this time. References: Berber E et al. Functional characterisation of the type 1 von Willebrand disease candidate VWF gene variants: p.M771I, p.L881R and p.P1413L. Blood Transfus. 2017;15(6):548-556. 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;109(1):112-121. James PD et al. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood. 2007;109(1):145-154. Veyradier A et al. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. Medicine (Baltimore). 2016;95(11):e3038. -

Oct 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VWF c.4238C>A (p.Pro1413Gln) variant has not been reported in individuals with VWF-related conditions in the published literature. A related variant affecting the same position of the VWF protein but producing a different amino acid change, p.Pro1413Leu, was identified in a study of Swedish families affected with Type 1 von Willebrand disease (PMID: 31249928 (2018)). The c.4238C>A (p.Pro1413Gln) variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on VWF mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Uncertain:1

Dec 23, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VWF c.4238C>A (p.Pro1413Gln) results in a non-conservative amino acid change in 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 251134 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4238C>A in individuals affected with Von Willebrand Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.70		Gain of catalytic residue at G1417 (P = 0);
MVP		0.89
MPC		0.91
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.61
gMVP		0.84
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61750079; hg19: chr12-6128346;