Criteria Specification Registry

Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.

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Criteria Specification

ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0

Description : Rule specifications for von Willebrand disease type 2A, 2B and 2M.

Version : 1.0.0

von Willebrand Disease VCEP

Released

7/9/2024

13:42:11

Rules for VWF

Applying VWD type 2 variant curation guidance is complex. If you are unsure how to apply these rule specifications after reading guidance materials provided below, it may be best not to use these guidelines. Alternatively, you are welcome to submit variants for the ClinGen VWD VCEP to curate for you.

Gene: VWF (HGNC:12726) HGNC Name: von Willebrand factor Transcripts: NM_000552.5 Disease: von Willebrand disease type 2A (MONDO:0015628) Mode of Inheritance: Autosomal dominant inheritance von Willebrand disease type 2B (MONDO:0015629) Mode of Inheritance: Autosomal dominant inheritance von Willebrand disease type 2M (MONDO:0015630) Mode of Inheritance: Autosomal dominant inheritance von Willebrand disease 2 (MONDO:0013304) Mode of Inheritance: Undetermined mode of inheritance von Willebrand disease (hereditary or acquired) (MONDO:0024574) Mode of Inheritance: Other

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: VWD type 2 is defined by qualitative defects in the VWF protein and not caused by null variants.
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Use with no specification except comparison variant must be classified as pathogenic using rules from the VWD VCEP. Modification Type: Gene-specific Moderate Use with no specification except comparison variant must be classified as likely pathogenic using rules from the VWD VCEP. Modification Type: Gene-specific Supporting Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Stand Alone Very Strong Use proposed SVI point recommendations for “Phenotype consistent with gene but not highly specific” if the proband meets PP4 criteria. Use “Phenotype highly specific for gene” phenotype consistency if the proband meets PP4_Moderate criteria. See Table 1 attached. Required 4 points. Modification Type: Disease-specific Strong Use proposed SVI point recommendations for “Phenotype consistent with gene but not highly specific” if the proband meets PP4 criteria. Use “Phenotype highly specific for gene” phenotype consistency if the proband meets PP4_Moderate criteria. See Table 1 attached. Required 2 points. Modification Type: Disease-specific Moderate Use proposed SVI point recommendations for “Phenotype consistent with gene but not highly specific” if the proband meets PP4 criteria. Use “Phenotype highly specific for gene” phenotype consistency if the proband meets PP4_Moderate criteria. See Table 1 attached. Required 1 point. Modification Type: Disease-specific Supporting Use proposed SVI point recommendations for “Phenotype consistent with gene but not highly specific” if the proband meets PP4 criteria. If the proband meets PP4_Moderate criteria, use a moderate or higher evidence weight (see above). See Table 1 attached. Required 0.5 point. Modification Type: Disease-specific Not Applicable
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. Stand Alone Very Strong Strong Either (1) In a transgenic animal model, must demonstrate minimal to no function. OR (2) The following types of assays using recombinant vWF are approved for each subtype: Subtype 2A = A multimerization assay in which the variant is expressed in a recombinant system (either independently or coexpressed with WT) resulting in abnormal multimers, with a reported loss of HMWM, AND, to confirm this is consistent with the variant's mechanism of disease, there must be a patient harboring the variant with a clinical assay also showing loss of HMWMs. This evidence must be published in a peer reviewed journal and a picture of the gel must be visible for evaluation. Subtype 2B = A GP1b or platelet binding assay indicating gain of function by increased binding at low doses of ristocetin Subtype 2M = Either (1) A GP1b or platelet binding assay OR (2) Collagen binding assay, indicating loss of function by decreased binding See attached spreadsheet for examples of approved assay instances to use for this rule code. There are no universal thresholds for these assays; however, the relevant results should be described as clinically significant if assays were performed in a clinical laboratory or statistically significant if pertaining to research findings. Modification Type: Disease-specific Moderate Supporting Subtype 2A = Either (1) a multimerization assay in which the variant is expressed in a recombinant system (either independently or coexpressed with WT) resulting in abnormal multimers, with a reported loss of HMWM. This evidence must be published in a peer reviewed journal and a picture of the gel must be visible for evaluation. (2) a ADAMTS susceptibility assay indicating increased susceptibility relative to WT. Modification Type: Disease-specific Not Applicable
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. Stand Alone Very Strong Appropriate to use code when there are 8 or more probands that meet the laboratory phenotype of the PP4 definition for a specific VWD type 2 phenotype (i.e. – all probands must qualify for a clinical diagnosis of the same VWD type 2 phenotype based on laboratory criteria stated under PP4). Modification Type: Disease-specific Strong Appropriate to use code when there are 4-7 probands that meet the laboratory phenotype of the PP4 definition for a specific VWD type 2 phenotype (i.e. – all probands must qualify for a clinical diagnosis of the same VWD type 2 phenotype based on laboratory criteria stated under PP4). Modification Type: Disease-specific Moderate Appropriate to use code when there are 2-3 probands that meet the laboratory phenotype of the PP4 definition for a specific VWD type 2 phenotype (i.e. – all probands must qualify for a clinical diagnosis of the same VWD type 2 phenotype based on laboratory criteria stated under PP4). Modification Type: Disease-specific Supporting Appropriate to use code when there is 1 proband that meets the laboratory phenotype of the PP4 definition for a specific VWD type 2 phenotype. Modification Type: Disease-specific Instructions: Do not apply this code for variants that meet BS1 or BA1 criteria. Do not count proband used for PP4 in this code's proband count. Not Applicable
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Rule does not apply due to benign variation being present throughout the gene.
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. Stand Alone Very Strong Strong Moderate Supporting Use code for variants with a popmax MAF of <0.0001 in gnomAD. Modification Type: Disease-specific,Gene-specific Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: These are dominant conditions, so this rule code does not apply.
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Stand Alone Very Strong Strong Moderate Use with no specification for type 2A and 2M. This rule code is not applicable to variants associated with type 2B disease, since type 2B is only associated with gain of function variants. Modification Type: Gene-specific Supporting Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Moderate Use code when previously reported variant reaches a pathogenic classification using the VWD Type 2 rule specifications. Previously reported variant can be associated with a different type of VWD. Code may also be applied when two previously reported variants reach a likely pathogenic classification using the VWD Type 2 rule specifications. Previously reported variants can be associated with a different type of VWD. Modification Type: General recommendation Supporting Use code when previously reported variant reaches a likely pathogenic classification using the VWD Type 2 rule specifications. Previously reported variant can be associated with a different type of VWD. Modification Type: General recommendation Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Use the PS2 code in lieu of using this code for de novo variants.
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. Stand Alone Very Strong Strong Moderate Appropriate to use when there are multiple families each reported to have two or more meioses. Modification Type: Disease-specific Supporting Appropriate to use when there are 2 or more meioses within a single family. Modification Type: Disease-specific Not Applicable
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Not applicable due to presence of benign variation throughout the VWF gene.
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting Appropriate to use for missense variants that have a REVEL score of greater or equal to 0.644 OR a SpliceAI score suggestive of a splicing defect (greater or equal to 0.5). Modification Type: Gene-specific Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Stand Alone Very Strong Strong Moderate The patient must have a clinical phenotype of excessive mucocutaneous bleeding and required laboratory values to use the PP4 rule code at the moderate strength. See Table 2A for required and consistent laboratory values. Modification Type: Disease-specific Supporting The patient must have a clinical phenotype of excessive mucocutaneous bleeding and required laboratory values to use the PP4 rule code at the supporting strength. See Table 2B for required and consistent laboratory values. Modification Type: Disease-specific Instructions: The PP4 code cannot be applied for variants that meet BA1 criteria. Not Applicable
PP5
Original ACMG Summary Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone Appropriate to use for variants with a Popmax MAF of >0.1 in gnomAD. Modification Type: Disease-specific,Gene-specific Very Strong Strong Moderate Supporting Not Applicable
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong Appropriate to use for variants with a Popmax MAF of >0.01 in gnomAD. Modification Type: Disease-specific,Gene-specific Moderate Supporting Not Applicable
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Not applicable due to the incomplete penetrance seen in VWD.
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: There are no available assays that can clearly and dependably show no damaging protein effects.
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Stand Alone Very Strong Strong Appropriate to use when two or more relatives have the phenotype consistent with VWD type 2 without harboring the variant identified in other affected family members. Additionally, there is not another established cause of type 2 VWD (e.g. - there are not multiple type 2 VWD diagnoses) segregating in the family. Modification Type: Disease-specific Moderate Supporting Appropriate to use when only one relative has the phenotype consistent with VWD type 2 without harboring the variant identified in other affected family members. Additionally, there is not another established cause of type 2 VWD (e.g. - there are not multiple type 2 VWD diagnoses) segregating in the family. Modification Type: Disease-specific Not Applicable
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: The VWF gene is not constrained for missense variation (gnomAD).
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Do not use due to potential of variant being associated with VWD 2N (recessive disease).
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: There are no known repetitive regions in the VWF gene without a known function.
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting Use for missense variants that have a REVEL score of less than or equal to 0.290 AND SpliceAI cutoff of <0.1. Use SpliceAI cutoff of <0.1 for other variant types. Modification Type: Gene-specific Not Applicable Comments: Not using at this time but will note CADD and SpliceAI scores and consider use during pilot testing.
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong Moderate Supporting A second variant in VWF may be considered an alternate molecular basis for disease when that variant is LP/P (as evaluated by the VWD VCEP) and fully explains the phenotype of the patient's reported VWD subtype. Modification Type: None Not Applicable
BP6
Original ACMG Summary Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Stand Alone Very Strong Strong Moderate Supporting Use SpliceAI for splicing predictor with a cutoff score of <0.1. Modification Type: General recommendation Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PS2_Very Strong, PS4_Very Strong) AND ≥ 1 Strong (PS1, PS2, PS3, PS4)

1 Very Strong (PS2_Very Strong, PS4_Very Strong) AND ≥ 2 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP4_Moderate)

1 Very Strong (PS2_Very Strong, PS4_Very Strong) AND 1 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP4_Moderate) AND 1 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Very Strong (PS2_Very Strong, PS4_Very Strong) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

≥ 2 Strong (PS1, PS2, PS3, PS4)

1 Strong (PS1, PS2, PS3, PS4) AND ≥ 3 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP4_Moderate)

1 Strong (PS1, PS2, PS3, PS4) AND 2 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Strong (PS1, PS2, PS3, PS4) AND 1 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

Likely Pathogenic

1 Very Strong (PS2_Very Strong, PS4_Very Strong) AND 1 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP4_Moderate)

1 Strong (PS1, PS2, PS3, PS4) AND 1 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP4_Moderate)

1 Strong (PS1, PS2, PS3, PS4) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

≥ 3 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP4_Moderate)

2 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Strong (PS1, PS2, PS3, PS4) AND 2 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP4_Moderate)

Benign

≥ 2 Strong (BS1, BS4)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS4) AND 1 Supporting (BS4_Supporting, BP4, BP5, BP7)

≥ 2 Supporting (BS4_Supporting, BP4, BP5, BP7)

Files & Images

Introduction to von Willebrand disease: This document summarizes von Willebrand disease for individuals who may be less familiar with this condition.

VWD type 2 List of Approved Functional Assays:: This document provides a list of functional assays that have been approved to use for PS3_Supporting by the VWD VCEP

VWD 2A/2M/2N functional assays: This document guides curators to determine which functional assays can be used to apply the PS3 rule code.

VWD Type 2 Rule Set Instructions for Use: Please refer to this document before using this rule set. This rule set only applies to VWF variants that are associated with a VWD type 2 diagnosis or no bleeding phenotype at all. VWD type 2 is complex to diagnose. There is flowchart for your reference to determine if this rule is appropriate for your variant.

VWD type 2 PS2/PM6 rule guidance: This document guides curators to determine if the PS2/PM6 rule code can be applied and, if so, at what strength.

VWD type 2 PP4 rule guidance: This document guides curators to determine if the PP4 rule code can be applied and, if so, at what strength.