Criteria Specification Registry

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Criteria Specification

ClinGen Pulmonary Hypertension Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BMPR2 Version 1.0.0

Description : ClinGen PH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BMPR2 Version 1.0.0

Version : 1.0.0

Pulmonary Hypertension VCEP

Released

3/1/2024

21:21:15

Rules for BMPR2

Gene: BMPR2 (HGNC:1078) HGNC Name: bone morphogenetic protein receptor type 2 Transcripts: NM_001204.7 Disease: pulmonary arterial hypertension (MONDO:0015924) Mode of Inheritance: Autosomal dominant 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 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: 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 the PVS1 decision tree guide. Modification Type: Gene-specific Strong Use the PVS1 decision tree guide. Modification Type: Gene-specific,Strength Moderate Use the PVS1 decision tree guide. Modification Type: Gene-specific,Strength Supporting Instructions: Biologically relevant transcript: NM_001204.7. LOF variants 5' or at c.2816 (exons 1-12) are expected to undergo NMD. Variants 3' to c.2816 (exon 13) are not expected to undergo NMD. Exon 13 does not contain regions critical for protein function and encodes <10% of the protein. Variant p.Trp13X (W13X) is known to escape NMD and produce a truncated protein (PMID: 20095988). Critical regions for protein function: ligand binding domain (aa 33-131), kinase domain (aa 203-504), heterodimerization domain (aa 485-492), and transmembrane domain (aa 151-171). For canonical splice variants, RNA splicing assay data is not necessary for applying PVS1; follow the decision tree based on the predicted effect of disrupted. splicing. Note that exons 1, 2, 3, 4, 6 are in-frame and a loss of a canonical splice acceptor/donor is not expected to result in NMD. Non-canonical splice site variants with RNA splicing assay data may be applicable for PVS1 according to the decision tree. The initiation codon is located in exon 1. There are approximately 27 in-frame downstream AUG initiation codons including 5 sites located in ex 4-6 having translation initiation scores similar or greater than the exon 1 codon (PMID: 20095988). However, there are many P/LP variants upstream of exons 4-6. 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 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. Modification Type: None Moderate Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change. Modification Type: Strength 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 Strong 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. Modification Type: No change Moderate Supporting 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 Use the BMPR2 functional assay document for guidance on allowable assays. Known variant validation controls (i.e. established pathogenic and benign variants) are required. One exception is if the same functional assay has been performed for the same variant by two independent groups and demonstrated to have the same functional effect by both groups. Also applicable for non-canonical splice site variants when RNA splice site assay data is available demonstrating abnormal splicing; positive and negative controls are required, preferably from patients and matched unaffected individuals. Note that splicing assay results may be tissue-sensitive. Modification Type: General recommendation,Gene-specific Moderate Supporting Use the BMPR2 functional assay document for guidance on allowable assays. If no known variant validation controls (i.e. established pathogenic and benign variants) were used, then score at the supporting strength. Modification Type: General recommendation Instructions: Can be applied additively with PP3 if applicable. 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 Prior observation of the variant in >4 unrelated patients with the same phenotype, and its absence in controls. Modification Type: Disease-specific Moderate Prior observation of the variant in >3 unrelated patients with the same phenotype, and its absence in controls. Modification Type: Disease-specific,Strength Supporting Prior observation of the variant in >1 unrelated patients with the same phenotype, and its absence in controls. Modification Type: Disease-specific,Strength Instructions: Affected individuals are defined as having a mean pulmonary artery pressure (mPAP) >20 mm Hg by right heart catheterization (RHC), or estimated by echocardiography if RHC is not advised. Strength is based on the number of unrelated PAH (heritable and/or idiopathic) probands identified with a variant. Unpublished, VCEP-approved internal case/variant data is acceptable if the proband does not have another pathogenic or likely pathogenic BMPR2 variant. Justification for the proband thresholds is provided in the “Data and citations related to PS4” attachment. PS4 (at any strength) and PM2_supporting can be used additively. 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 Variant changes a critical amino acid. Extracellular domain: p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123. Kinase domain: p.Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Arg491. KD heterodimerization: p.Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Leu492. Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated non-critical/not necessary for kinase activity based on a luciferase assay (apply BS3). Modification Type: Gene-specific,Strength Moderate Variant changes an amino acid in the extracellular domain (aa 33-131) or kinase domain (aa 203-504) but without functional evidence indicating critical or non-critical. Note that p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123, Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Arg491, and Leu492 have been demonstrated critical (apply PM1_strong). Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated non-critical/not necessary for kinase activity based on a luciferase assay (apply BS3). Modification Type: Gene-specific Supporting Instructions: Well-established functional domains for BMPR2 include the extracellular (ligand-binding) domain, protein kinase domain, and heterodimerization motif within the kinase domain. Strong evidence based on evolutionary conservation, in vitro functional assays, and protein structural analyses indicates the critical (or non-critical) nature of specific amino acid residues within each of these domains (see attached “Data and citations related to PM1”). Strength should be applied accordingly. Not Applicable
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 Present at <0.01% among gnomAD controls, using the subpopulation with the highest frequency and at least 1,000 allele counts. Caveat: Population data for indels may be poorly called by next generation sequencing. Modification Type: Disease-specific Instructions: PAH has a prevalence of 15-50 cases/million individuals and the population allele frequency threshold for PM2 is based on this frequency. There is no evidence for a genetic ancestry effect on PAH prevalence, so the use of any sub-population data is acceptable (as long as there is a minimum allele count of 1,000). As specified by the SVI WG, PM2 is scored at the supporting level only. Note that PM2_supporting and PS4 (at any strength) can be used additively. 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: PAH is autosomal dominant.
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 Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. 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 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. Also applicable for variants affecting the same splice site as a confirmed splice variant with similar or worse splicing in silico predictions Modification Type: General recommendation Supporting Novel missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before. Modification Type: Strength 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 Assumed de novo, but without confirmation of paternity and maternity. Modification Type: No change Supporting Not Applicable
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 Co-segregation with disease in ≥7 affected family members. Modification Type: Strength Moderate Co-segregation with disease in ≥5 affected family members. Modification Type: Strength Supporting Co-segregation with disease in ≥3 affected family members. Modification Type: Strength Instructions: Note: PAH exhibits variable age of onset and incomplete penetrance. Three levels of evidence are applied based on autosomal dominant likelihood ratios of 10 (3 meioses, LOD 0.9, supporting), 30 (5 meioses, LOD 1.5, moderate), and 100 (7 meioses, LOD 2.1, strong) provided that PM2 (absent or rare in large population cohorts) is met. Demonstration of segregation in more than one family is not necessary as BMPR2 is a well-established PAH gene. PMID: 29300372. 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: BMPR2 is not constrained for missense variants.
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 REVEL ≥0.75 for missense variants or Splice AI ≥0.2 for non-canonical splice variants. No up/downgrading. If no REVEL score or SpliceAI prediction is available, then CADD ≥20 can be used. Note: can be applied additively with PS3 if applicable. Modification Type: General recommendation 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 Supporting Not Applicable Comments: PAH does not have a single genetic etiology.
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 Allele frequency is above 1% in gnomAD, including any sub-population with at least 1,000 allele counts. Modification Type: Disease-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 Allele frequency >=0.1% among gnomAD controls, using the subpopulation with the highest frequency and at least 1,000 allele counts. Modification Type: Disease-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 Observed in ≥3 homozygotes in gnomAD controls or reported in the literature (healthy adult individuals). Modification Type: Disease-specific,Gene-specific Moderate Supporting Observed in ≥2 homozygotes in gnomAD controls or reported in the literature (healthy adult individuals). Modification Type: Disease-specific,Gene-specific Instructions: Strength based on number of homozygotes observed among gnomAD controls. Criteria not applicable for heterozygotes as BMPR2 variants exhibit incomplete penetrance. 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 Use the BMPR2 functional assay document for acceptable assays and guidance. Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated non-critical/not necessary for kinase activity based on a luciferase assay (apply BS3). Note that p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123, Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Arg491, and Leu492 have been demonstrated critical (apply PM1_strong). Modification Type: Gene-specific Moderate Supporting 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 Lack of variant segregation in affected members of a family. Modification Type: No change Moderate Supporting Instructions: Lack of disease segregation among BMPR2 variant carriers should not be scored due to low penetrance of PAH variants in families. Lack of variant segregation in affected family members should be scored. 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: Both LOF and missense variants are known to cause PAH.
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: BMPR2 variants are not fully penetrant.
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 In frame-deletions/insertions in a repetitive region without a known function. Modification Type: No change 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 REVEL ≤0.25 for missense variants or Splice AI ≤0.1 for non-canonical splice variants. No up/downgrading. If no REVEL or. Splice AI available, then CADD ≤ 10 can be used. Modification Type: General recommendation 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: BMPR2 is the major causal PAH gene.
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 If BP7 is met and negative RNA splicing assay data is available, then apply BP7_strong. Acceptable splicing assays should have positive and negative controls, preferably from patients and matched unaffected individuals. Note that splicing assay results may be tissue-sensitive. Modification Type: Strength Moderate Supporting 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. Applicable after assignment of BP4 for no adverse splicing predictions, and inclusive of exonic and intronic variants. Not applicable for synonymous variants located at the first base or the last three bases of an exon. Modification Type: No change Instructions: Use default Splice AI predictions. Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1) AND ≥ 1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong)

1 Very Strong (PVS1) AND ≥ 2 Moderate (PVS1_Moderate, PS1_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate)

1 Very Strong (PVS1) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate) AND 1 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3)

1 Very Strong (PVS1) AND ≥ 2 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3)

≥ 2 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong) AND ≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate) AND ≥ 2 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate) AND ≥ 4 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3)

Likely Pathogenic

1 Very Strong (PVS1) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong) AND ≥ 2 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3)

≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate)

2 Moderate (PVS1_Moderate, PS1_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate) AND ≥ 2 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3)

1 Moderate (PVS1_Moderate, PS1_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate) AND ≥ 4 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate)

Benign

≥ 2 Strong (BS1, BS2, BS3, BS4, BP7_Strong)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BS3, BS4, BP7_Strong) AND 1 Supporting (BS2_Supporting, BP3, BP4, BP7)

≥ 2 Supporting (BS2_Supporting, BP3, BP4, BP7)

Files & Images

Point-based system for variant classification: Point-based system for variant classification

Response to SVI WG review 2_8.22.2023:

Data and citations related to PS4:

Data and citations related to PM1:

BMPR2 functional assay guidelines related to PS3:

PH VCEP Pilot Results_BMPR2:

PVS1_DecisionTree_BMPR2: