owencqueen/cgbench_data huggingface dataset:
Gene: VWF (HGNC:12726)
Evidence Code: PVS1 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: PS1 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: PS1 — Strong
Modification Type: Gene-specific
Use with no specification except comparison variant must be classified as pathogenic using rules from the VWD VCEP.
Gene: VWF (HGNC:12726)
Evidence Code: PS1 — Moderate
Modification Type: Gene-specific
Use with no specification except comparison variant must be classified as likely pathogenic using rules from the VWD VCEP.
Gene: VWF (HGNC:12726)
Evidence Code: PS2 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: PS2 — Very Strong
Modification Type: Disease-specific
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.
Gene: VWF (HGNC:12726)
Evidence Code: PS2 — Strong
Modification Type: Disease-specific
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.
Gene: VWF (HGNC:12726)
Evidence Code: PS2 — Moderate
Modification Type: Disease-specific
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.
Gene: VWF (HGNC:12726)
Evidence Code: PS2 — Supporting
Modification Type: Disease-specific
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.
Gene: VWF (HGNC:12726)
Evidence Code: PS3 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific
Either (1) in a transgenic animal model, must demonstrate minimal to no function. (2) a Factor VIII binding assay using recombinant vWF resulting in decreased binding compared to WT.


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.
Gene: VWF (HGNC:12726)
Evidence Code: PS4 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: PM1 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: PM2 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific,Gene-specific
Use code for variants with a popmax MAF of <0.005 in gnomAD.
Gene: VWF (HGNC:12726)
Evidence Code: PM3 — Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase.
Gene: VWF (HGNC:12726)
Evidence Code: PM3 — Very Strong
Modification Type: Disease-specific
Use SVI recommended point system for this code for probands with a VWD type 2N diagnosis. Total of 4 points required.
Gene: VWF (HGNC:12726)
Evidence Code: PM3 — Strong
Modification Type: Disease-specific
Use SVI recommended point system for this code for probands with a VWD type 2N diagnosis. Total of 2 points required.
Gene: VWF (HGNC:12726)
Evidence Code: PM3 — Moderate
Modification Type: Disease-specific
Use SVI recommended point system for this code for probands with a VWD type 2N diagnosis. Total of 1 point required.
Gene: VWF (HGNC:12726)
Evidence Code: PM3 — Supporting
Modification Type: Disease-specific
Use SVI recommended point system for this code for probands with a VWD type 2N diagnosis. Total of 0.5 points required.
Gene: VWF (HGNC:12726)
Evidence Code: PM4 — Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: VWF (HGNC:12726)
Evidence Code: PM4 — Moderate
Modification Type: None
Use with no specification.
Gene: VWF (HGNC:12726)
Evidence Code: PM5 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: PM5 — Moderate
Modification Type: Disease-specific,General recommendation
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.
Gene: VWF (HGNC:12726)
Evidence Code: PM5 — Supporting
Modification Type: Disease-specific,General recommendation
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.
Gene: VWF (HGNC:12726)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: VWF (HGNC:12726)
Evidence Code: PP1 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: PP1 — Strong
Modification Type: Disease-specific
Appropriate to use when a proband has three affected family members.
Gene: VWF (HGNC:12726)
Evidence Code: PP1 — Moderate
Modification Type: Disease-specific
Appropriate to use when a proband has two affected family members.
Gene: VWF (HGNC:12726)
Evidence Code: PP1 — Supporting
Modification Type: Disease-specific
Appropriate to use when a proband has one affected family member.
Gene: VWF (HGNC:12726)
Evidence Code: PP2 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: PP3 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: PP3 — Supporting
Modification Type: Gene-specific
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).
Gene: VWF (HGNC:12726)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: VWF (HGNC:12726)
Evidence Code: PP4 — Moderate
Modification Type: Disease-specific
The patient must have a clinical phenotype of excessive mucocutaneous bleeding and required laboratory values to use the PP4 rule code, including a low factor VIII activity level and evidence of decreased VWF:FVIII binding.


Additional consistent information should be noted but is not required, including either normal or low VWF:Ag, normal high molecular weight multimers, and sequencing with duplication/deletion analysis of the F8 gene.
Gene: VWF (HGNC:12726)
Evidence Code: 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.
Gene: VWF (HGNC:12726)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: VWF (HGNC:12726)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific,Gene-specific
Appropriate to use for variants with a Popmax MAF of >0.1 in gnomAD.
Gene: VWF (HGNC:12726)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: VWF (HGNC:12726)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific,Gene-specific
Appropriate to use for variants with a Popmax MAF of >0.01 in gnomAD.
Gene: VWF (HGNC:12726)
Evidence Code: BS2 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: BS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Gene: VWF (HGNC:12726)
Evidence Code: BS4 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: BS4 — Strong
Modification Type: Disease-specific
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.
Gene: VWF (HGNC:12726)
Evidence Code: BS4 — Supporting
Modification Type: Disease-specific
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.
Gene: VWF (HGNC:12726)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: VWF (HGNC:12726)
Evidence Code: BP2 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: VWF (HGNC:12726)
Evidence Code: BP4 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: BP4 — Supporting
Modification Type: Gene-specific
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.
Gene: VWF (HGNC:12726)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: VWF (HGNC:12726)
Evidence Code: BP5 — Supporting
Modification Type: None
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.
Gene: VWF (HGNC:12726)
Evidence Code: 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.
Gene: VWF (HGNC:12726)
Evidence Code: BP7 — 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.
Gene: VWF (HGNC:12726)
Evidence Code: BP7 — Supporting
Modification Type: Disease-specific
Use SpliceAI for splicing predictor with a cutoff score of 0.