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 Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Description : ACMG variant classification (PAH) version 2.0

Version : 2.0.0 Release Notes :

4/19/24: Please see response to SVI comments in the Word document. All suggestions are addressed; specifically, changes to PM1 and PS3.

Version 2 has many changes and updates. See attached Word document for specifics. response to SVI comments are in PM1 and PP3, with attachments for PVS1 and PS3.

Phenylketonuria VCEP

Released

7/16/2024

15:03:44

Rules for PAH

Version 2.0

Gene: PAH (HGNC:8582) HGNC Name: phenylalanine hydroxylase Transcripts: Disease: phenylketonuria (MONDO:0009861)

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 Applicable as described in Tayoun et al. 2018. Any nonsense or frameshift variant occurring upstream of c.1285 Any canonical splice site predicted to disrupt reading frame and undergo nonsense mediated decay PVS1 (RNA): splicing assay data - assays demonstrating a variant leads to aberrant splicing profile that can be categorized against a PVS1 decision tree Use the PVS1 decision tree to determine code strength Applicable as described in Walker et al. (PMID: 36865205) Modification Type: Disease-specific Strong Use PVS1_strong with: Any nonsense or frameshift variant occurring downstream of c.1285 Any canonical splice site predicted to preserve reading frame (skipping of exons 1, 9, 10) or affect the last exon (exon 13) Initiator codon variant Modification Type: Disease-specific Moderate Supporting 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 predicted splicing impact as a previously classified (likely) pathogenic variant Applicable as described in Walker et al. (PMID: 36865205) Modification Type: Disease-specific Moderate 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 Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Only applicable when proband has a known pathogenic variant in trans with the de novo variant. Modification Type: Disease-specific 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 Moderate Functional studies with sufficient analyses to calculate OddsPath reaching strong have not been identified. Therefore, the strength of this criteria is modified to PS3_moderate or PS3_supporting for future or existing studies. In vitro enzyme activity <50% compared to wild type controls. Expression systems placing the mutant (and wild-type) cDNAs into plasmid vectors and introducing these into human or other mammalian host cells, which is the closest available approximation to the in vivo situation (e.g., COS cells) (Trunzo et al. Gene. 2016. 594:138-143. PMID: 27620137). With ≥11 benign/pathogenic variant controls used in assay NOTE: no papers that meet PS3_Moderate criteria have been identified by the PAH VCEP at time of this specification update. However, there may be future studies that meet the above criteria where a moderate level of evidence can be applied. Modification Type: Disease-specific Supporting In vitro enzyme activity ≤50% compared to wild type controls with ≤10 benign/pathogenic variant controls used in assay Modification Type: Strength Not Applicable Comments: Functional studies with sufficient analyses to calculate OddsPath reaching strong have not been identified. Therefore, the strength of this criteria is modified to PS3_moderate or PS3_supporting for future or existing studies.
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 Supporting Not Applicable Comments: This criterion is not applicable for PAH. For proband counting, use PM3 criterion.
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 Active site residues in PAH include: Tyr138, Arg158, Val245, Tyr268, Thr278, Pro279, Glu289, Ala300, Asp315, Phe331, Ala345, Gly346, Ser349, Tyr377 Substrate binding residues in PAH are: 46-48, 63-69 Cofactor binding residues in PAH are: His285, His290, Glu330, 246-266, 280-283, 322-326, 377-379 Do not apply if PP3_Strong applies Modification Type: Gene-specific Supporting 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 Threshold <0.0002 (0.02%) The 0.0002 cutoff is based on disease frequency of 1:12,000 and the most common PAH pathogenic variant, R408W, the ExAC frequency is 0.0006594 (ExAC MAF: 0.001109 74/66718 European Non-Finnish) and gnomAD overall: 0.0009056 (gnomAD MAF: 0.001728 219/126,700 European Non-Finnish). Modification Type: Strength 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 Applicable as described in SVI recommendations for in trans criterion Modification Type: Strength Strong Applicable as described in SVI recommendations for in trans criterion Modification Type: Strength Moderate Applicable as described in SVI recommendations for in trans criterion Modification Type: Strength Supporting Applicable as described in SVI recommendations for in trans criterion Modification Type: Strength 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 Applicable as described 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 Applicable as described. Modification Type: No change Supporting Applicable when the different missense change is likely pathogenic. 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 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 3 affected segregations + 0 unaffected segregations OR 2 affected segregations + 3 unaffected segregations Modification Type: Strength Moderate 2 affected segregations + 0 unaffected segregations Modification Type: Strength Supporting 1 affected family member + 3 unaffected segregations Modification Type: Strength 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
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 Applicable as described in Pejaver et al (PMID: 36413997): REVEL score ≥0.932 for missense variants PP3 + PM1 should not exceed Strong Modification Type: Strength Moderate Applicable as described in Pejaver et al (PMID: 36413997): REVEL score 0.773 - 0.932 for missense variants Modification Type: Strength Supporting Applicable as described in Pejaver et al. (PMID: 36413997): REVEL score of 0.644 - 0.733 for missense variants In frame deletion or insertion predicted deleterious by 2 out of 3 tools (PROVEAN, MutationTaster, MutPred-InDel) Predicted impact on splicing by SpliceAI (score >0.5) Modification Type: Strength Instructions: Per SVI recommendations (PMID: 36865205), PP3 should not be used for variants with experimental evidence of altered splicing; for variants without experimental evidence of altered splicing, PP3 can be used for variants that have a SpliceAI delta score of ≥0.2. 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 Plasma phenylalanine concentration persistently above 120 µmol/L (2mg/dL), and either normal urine pterins and normal DHPR activity, or sequencing of genes in the BH4 cofactor metabolism pathway to exclude a defect of BH4 cofactor metabolism. Modification Type: Disease-specific,Strength Supporting A plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) without analysis of urine pterins, DHPR activity, or sequencing to exclude defects of BH4 cofactor metabolism. Modification Type: Strength 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 An allele frequency ≥0.015 (1.5%), which is calculated with genetic heterogeneity of 90% to account for defects of BH4 metabolism, and penetrance of 80% to account for individuals who come to attention after becoming clinically symptomatic. 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 ≥0.002 (0.2%) 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 Only to be used when variant is observed in the homozygous state in a healthy adult. Modification Type: None 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 Moderate Supporting In vitro enzyme activity >85% compared to wild type Expression systems: placing the mutant (and wildtype) cDNA into plasmid vectors and introducing these into host cells. Transiently transfected human or other mammalian host cells are the closest available approximation to the in vivo situation (e.g., COS cells) (Trunzo, et al. Gene. 2016. 594:138-143). Modification Type: Disease-specific,Strength 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 Applicable as described Modification Type: None 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
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
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
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 Applicable as described in Pejaver et al. Modification Type: No change Moderate Applicable as described in Pejaver et al. Modification Type: No change Supporting Applicable as described in Pejaver et al. REVEL score of 0.183 - 0.290 for missense variants In frame deletion or insertion predicted benign by PROVEAN, MutationTaster, and MutPred-InDel No predicted impact on splicing by SpliceAI (score <0.1) Modification Type: Gene-specific,None Instructions: BP4_very strong: applicable as described in Pejaver et al. 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 Applicable as described Modification Type: No change 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 Applicable as described by Walker et al. (PMID: 36865205). Modification Type: Strength Moderate Supporting Per SVI recommendations (PMID: 36865205), use BP7 only if BP4 is met; for variants with experimental evidence supporting that they do not alter splicing, use BP7_strong (RNA) intronic variants must be outside +7/-21 nt exonic variants must be outside first and last 3 bases of exon Modification Type: Gene-specific,None Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1, PM3_Very Strong) AND ≥ 1 Strong (PVS1_Strong, PS1, PS2, PM3_Strong, PP1_Strong, PP3_Strong)

1 Very Strong (PVS1, PM3_Very Strong) AND ≥ 2 Moderate (PS3_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Very Strong (PVS1, PM3_Very Strong) AND 1 Moderate (PS3_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND 1 Supporting (PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

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

≥ 2 Strong (PVS1_Strong, PS1, PS2, PM3_Strong, PP1_Strong, PP3_Strong)

1 Strong (PVS1_Strong, PS1, PS2, PM3_Strong, PP1_Strong, PP3_Strong) AND ≥ 3 Moderate (PS3_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PM3_Strong, PP1_Strong, PP3_Strong) AND 2 Moderate (PS3_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Strong (PVS1_Strong, PS1, PS2, PM3_Strong, PP1_Strong, PP3_Strong) AND 1 Moderate (PS3_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

Likely Pathogenic

1 Very Strong (PVS1, PM3_Very Strong) AND 1 Moderate (PS3_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PM3_Strong, PP1_Strong, PP3_Strong) AND 1 Moderate (PS3_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PM3_Strong, PP1_Strong, PP3_Strong) AND ≥ 2 Supporting (PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

≥ 3 Moderate (PS3_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

2 Moderate (PS3_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Moderate (PS3_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Strong (PVS1_Strong, PS1, PS2, PM3_Strong, PP1_Strong, PP3_Strong) AND 2 Moderate (PS3_Moderate, PM1, PM3, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

Benign

≥ 2 Strong (BS1, BS2, BS4, BP4_Strong, BP7_Strong)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BS4, BP4_Strong, BP7_Strong) AND 1 Supporting (BS3_Supporting, BP4, BP5, BP7)

≥ 2 Supporting (BS3_Supporting, BP4, BP5, BP7)

Files & Images

PAH PVS1 decision tree:

PAH PS3 functional data:

PAH PP3 REVEL data explanation: