Criteria Specification Registry

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Criteria Specification

ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP1BA Version 1.0.0

Description : Rule specifications for Bernard-Soulier syndrome associated with the GP1BA gene.

Version : 1.0.0

Platelet Disorders VCEP

Released

2/12/2025

13:36:02

Rules for GP1BA

Gene: GP1BA (HGNC:4439) HGNC Name: glycoprotein Ib platelet subunit alpha Transcripts: NM_000173.7 Disease: Bernard-Soulier syndrome (MONDO:0009276) Mode of Inheritance: Autosomal recessive inheritance

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 Use GP1BA modified decision tree as per SVI WG. Modification Type: Gene-specific Strong Use GP1BA modified decision tree as per SVI WG. Modification Type: Gene-specific Moderate Use GP1BA modified decision tree as per SVI WG. Modification Type: Gene-specific Supporting Use GP1BA modified decision tree as per SVI WG. Modification Type: Gene-specific Instructions: See GP1BA modified decision tree below. Not Applicable
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 as originally specified, but the comparison variant must reach a pathogenic classification using these rule specifications in order to apply code. Modification Type: General recommendation Moderate Use as originally specified, but the comparison variant must reach a likely pathogenic classification using these rule specifications in order to apply code. Modification Type: General recommendation 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. See further instruction below. Total of 4 points. Modification Type: Disease-specific Strong Use proposed SVI point recommendations. See further instruction below. Total of 2 points. Modification Type: Disease-specific Moderate Use proposed SVI point recommendations. See further instruction below. Total of 1 point. Modification Type: Disease-specific Supporting Use proposed SVI point recommendations. See further instruction below. Total of 0.5 point. Modification Type: Disease-specific Instructions: Only applicable when proband has a known pathogenic or likely pathogenic variant according to the BSS rule specifications along with the de novo variant. Only use “highly specific phenotype” scoring if all three BSS genes were sequenced. Otherwise use the “consistent but not highly specific” scoring. See further instructions below. 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 In a transgenic animal model, must demonstrate minimal to no function. Modification Type: Disease-specific Moderate Supporting Functional assays measuring quantity of GP1ba expression on cell surface measured by flow cytometry analysis of GPIb and GPIX when there is absent or near absent expression, >75% reduction (see spreadsheet for more detail). 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 Strong Moderate See instructions below for scoring heterozygous individuals only. Moderate strength applicable for score of 2+ points. Modification Type: Disease-specific Supporting See instructions below for scoring heterozygous individuals only. Supporting strength applicable for scores ranging from 1-1.75 Modification Type: Disease-specific Instructions: According to Bragadottir, et al, individuals heterozygous for Bernard-Soulier syndrome variants are considered informative due to measurable, quantitative abnormalities relevant to the disease (PMID: 25370924). Caveats, (1) The variant must be sufficiently rare, meeting PM2_supporting (2) There must be an assumed unrelated biallelic BSS patient, meeting PP4, before heterozygotes are considered (3) A single proband of a family can be included in either PM3 (biallelic proband) or PS4 (monoallelic proband), not both (4) Any additional family members are not included in PS4, they may be considered for segregation in PP1. Scoring: significantly reduced surface expression of GP1b measured by flow cytometry – 0.5pt OR giant platelets (MPD >7 microns) or macrothrombocytopenia (MPV >12 fL and platelet count <150x10^9/L) – 0.25pt Not Applicable Comments: Rule does not apply due to rarity of disorder and lack of appropriate studies.
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 Disulfide bonds in GPIb are well-established as critical to function, both for interaction with GPIX (PMID: 12036872) and receptor binding to von Willebrand factor (PMID: 18647229). PM1 can be applied when the following cysteine residues (at which there are no known benign variants) are altered: 20, 33, 225, 227, 264, 280, 526, 527. Modification Type: Gene-specific Supporting Not Applicable Comments: Rule does not apply due to gene being polymorphic.
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 gnomAD MAF of less than or equal to 0.0001114. 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 Use proposed SVI point recommendations. Both variants must be classified using these rule specifications. Modification Type: Disease-specific Strong Use proposed SVI point recommendations. Both variants must be classified using these rule specifications. Modification Type: Disease-specific Moderate Use proposed SVI point recommendations. Both variants must be classified using these rule specifications. Modification Type: Disease-specific Supporting Use proposed SVI point recommendations. Both variants must be classified using these rule specifications. Modification Type: Disease-specific Instructions: In trans variants classified as a variant of uncertain significance, as per the GP1BA rule specifications, must meet PM2_supporting to be scored. Conversely, in trans variants that meet a pathogenic or likely pathogenic classification using the GP1BA rule specifications do not have to meet PM2_supporting criteria; however, they cannot meet BS1 or BA1 criteria. See PM3 instructions below for further detail. Not Applicable
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. Modification Type: No change 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 as originally specified, but the comparison variant must reach a pathogenic classification using the these rule specifications in order to apply code. Modification Type: General recommendation Supporting Use as originally specified, but the comparison variant must reach a likely pathogenic classification using the these rule specifications in order to apply code. 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 PS2 for de novo cases in lieu of this rule code.
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 See instructions below for scoring system. Total segregation score 3+ points. Modification Type: Disease-specific Moderate See instructions below for scoring system. Total segregation score 2-2.75 points. Modification Type: Disease-specific Supporting See instructions below for scoring system. Total segregation score 1-1.75 points. Modification Type: Disease-specific Instructions: For Bernard-Soulier syndrome (BSS), segregation of the variant in a pedigree is considered informative in the case of both additional relatives with BSS and in heterozygous relatives with measurable, quantitative abnormalities relevant to the disease. Caveat, there must be a biallelic BSS patient, meeting PP4, before segregation points are awarded. Additionally, heterozygotes used for PP1 cannot be applied to PS4. Segregation scoring: (1) Proband – 0pt (proband should be accounted for in PP4 or PS4) (2) BSS affected relative with the same biallelic variant(s) identified in the proband – 1pt (3) Relative heterozygous for the variant under assessment with a relevant measurable, quantitative abnormality. Caveat, only score one parent of a homozygous proband in a consanguineous pedigree. 3a. significantly reduced surface expression of GP1b measured by flow cytometry – 0.5pt OR 3b. giant platelets (MPD >7 microns) or macrothrombocytopenia (MPV >12 fL and platelet count <150x10^9/L) – 0.25pt 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: This rule does not apply because BSS is a rare disease and this gene is not constrained for missense variation (gnomAD).
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 REVEL score of ≥0.773 based on recommendations of Pejaver et al., 2022 (PMID: 36413997). Modification Type: Gene-specific Supporting REVEL score of ≥0.644 (to <0.773), based on recommendations of Pejaver et al., 2022 (PMID: 36413997). OR suggested splicing effect using SpliceAI greater than 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 Must meet both criteria: 1)Proband with platelet aggregation study absent for ristocetin and present for all other agonists OR flow cytometry or Western blot less than 10% expression of GPIba. 2)Proband must have full sequencing of all three BSS genes (GP1BA, GP1BB and GP9) and deletion/duplication analysis. Modification Type: Disease-specific Supporting Proband with platelet aggregation study absent for ristocetin and present for all other agonists, OR Flow cytometry or Western blot less than 10% expression of GPIba. Modification Type: Disease-specific 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 gnomAD MAF of greater than or equal to 0.001 (or 0.1%). Modification Type: 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 gnomAD MAF greater than or equal to 0.0005 but less than 0.001. Modification Type: 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 Use this rule with 1 or more homozygotes who are unaffected (proven with aggregometry OR flow cytometry AND normal platelet count AND normal platelet size). Modification Type: Disease-specific Moderate Supporting Not Applicable
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 Must demonstrate normal aggregometry in a transgenic mouse model Modification Type: Disease-specific Moderate Supporting In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function as compared to wildtype. Modification Type: Disease-specific Not Applicable
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 Variant not tracking in an affected family member. Modification Type: Disease-specific Moderate Supporting 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: Rule does not apply as truncating variants do not predominate and missense variants are a known cause of disease.
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 Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant). Modification Type: Disease-specific Not Applicable
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 Use with no specification Modification Type: None Not Applicable
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 For a missense variant apply when REVEL score is < 0.290, based on recommendations of Pejaver et al., 2022 (PMID: 36413997) AND SpliceAI score is zero. OR for a synonymous or intronic variant apply when SpliceAI score is zero. Modification Type: Gene-specific Instructions: Determine REVEL and Splice AI cutoff before applying this code. Do not use if PP3 is met. Not Applicable
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 Not Applicable Comments: Do not use this rule as an individual can be a carrier of an unrelated pathogenic variant for a recessive disorder.
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 to rule out possible splicing defect (score = 0.2 or less) and reference PhyloP (score = 1.5 or less) to assess conservation. Modification Type: Gene-specific Instructions: Can be used for intronic variants. Also, can be used in combination with BP4. Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND ≥ 1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PP1_Strong)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND ≥ 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND 1 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

≥ 2 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PP1_Strong)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PP1_Strong) AND ≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PP1_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PP1_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

Likely Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PP1_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PP1_Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PP1_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND 1 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

Benign

≥ 2 Strong (BS1, BS2, BS3, BS4)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BS3, BS4) AND 1 Supporting (BS3_Supporting, BP2, BP3, BP4, BP7)

≥ 2 Supporting (BS3_Supporting, BP2, BP3, BP4, BP7)

Files & Images

PVS1 flowchart for GP1BA gene:

Instructions for PS2_PM6 code use: Further detail for use of the combined PS2 and PM6 rule codes.

Guidance for Combining Pathogenic and Benign Rule Codes: A point counting policy is used for variants where pathogenic and benign rule codes can be applied rather than defaulting to a VUS classification. This document illustrates how to combine pathogenic and benign rule codes.

PS3_Supporting Functional Assays: This file includes eligible functional assays for use of the PS3_supporting code.

Instructions for PM3 code use: Further detail for use of the PM3 rule code.

References

1. Savoia A Pastore A et al. Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations. Haematologica (2011) 96 (3) p. 417-23. 10.3324/haematol.2010.032631 21173099