owencqueen/cgbench_data huggingface dataset:
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: PVS1 — Very Strong
Modification Type: None
Null variant in a gene where loss of function is a known mechanism of disease.
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: PS1 — Strong
Modification Type: None
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: PS2 — Strong
Modification Type: None
De novo (paternity confirmed) in a patient with the disease and no family history.
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific
Well-established in vitro or in vivo functional studies supportive of a damaging effect




PAH enzyme activity assay demonstrating enzyme activity <50%


RT-PCR evidence of missplicing for non-canonical intronic variants
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
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: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: PM2 — Moderate
Modification Type: Disease-specific
Absent/rare from controls in an ethnically-matched cohort population sample.




Threshold: <0.0002 (0.02%).
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: PM3 — Very Strong
Modification Type: Strength
For recessive disorders, detected in trans with a pathogenic variant.




4 compound heterozygotes with 3 P/LP variants OR


2 compound heterozygotes with 2 P/LP variants AND 4 homozygotes OR


3 compound heterozygotes with 2 P/LP variants AND 2 homozygotes
Gene: PAH (HGNC:8582)
Evidence Code: PM3 — Strong
Modification Type: Strength
For recessive disorders, detected in trans with a pathogenic variant.




Compound heterozygous with 2 P/LP variants OR


Compound heterozygous with 1 P/LP variant AND 2 homozygotes
Gene: PAH (HGNC:8582)
Evidence Code: PM3 — Moderate
Modification Type: None
For recessive disorders, detected in trans with a pathogenic variant.
Gene: PAH (HGNC:8582)
Evidence Code: PM3 — Supporting
Modification Type: Strength
Detected in trans with another variant:




2 compound heterozygotes (with VUS in trans)


2 homozygotes (allele drop out excluded)
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: PM4 — Moderate
Modification Type: None
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: PM5 — Moderate
Modification Type: None
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Gene: PAH (HGNC:8582)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: PP1 — Strong
Modification Type: Strength
Co-segregation with disease in multiple affected family members:




3 affected segregations + 0 unaffected segregations OR


2 affected segregations + 3 unaffected segregations
Gene: PAH (HGNC:8582)
Evidence Code: PP1 — Moderate
Modification Type: Strength
Co-segregation with disease in multiple affected family members




2 affected segregations + 0 unaffected segregations
Gene: PAH (HGNC:8582)
Evidence Code: PP1 — Supporting
Co-segregation with disease in multiple affected family members




1 affected family member + 3 unaffected segregations
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: PP3 — Supporting
Multiple lines of computational evidence support a deleterious effect on the gene or gene product
Gene: PAH (HGNC:8582)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: PAH (HGNC:8582)
Evidence Code: PP4 — Moderate
Modification Type: Strength,Disease-specific
Plasma Phe >120 µmol/L and exclusion of a defect of BH4 cofactor metabolism.
Gene: PAH (HGNC:8582)
Evidence Code: PP4 — Supporting
Phenotype specific for disease with single genetic etiology.
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: PAH (HGNC:8582)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Allele frequency above 0.015 (1.5%)
Gene: PAH (HGNC:8582)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: PAH (HGNC:8582)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Allele frequency greater than expected for disease (>0.002, 0.2%)
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: BS2 — Strong
Modification Type: None
Observed in the homozygous state in a healthy adult
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: BS3 — Supporting
Modification Type: Strength,Disease-specific
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function




Enzyme activity >85%
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: BS4 — Strong
Lack of segregation in affected members of a family.
Gene: PAH (HGNC:8582)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: BP4 — Supporting
Modification Type: None
Multiple lines of computational evidence suggest no impact on gene or gene product
Gene: PAH (HGNC:8582)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: PAH (HGNC:8582)
Evidence Code: BP5 — Supporting
Modification Type: None
Variant found in a case with an alternate molecular basis for disease
Gene: PAH (HGNC:8582)
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: PAH (HGNC:8582)
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: PAH (HGNC:8582)
Evidence Code: BP7 — Supporting
Modification Type: None
A synonymous (silent) 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.