owencqueen/cgbench_data huggingface dataset:
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: PVS1 — Very Strong
Modification Type: None
Null variant in a gene where loss of function is a known mechanism of disease or in frame loss of an exon that contains residues involved in the active site of GAA.




Any nonsense, frameshift, or splice variant creating a premature stop codon before codon 916.


In frame deletions of an entire exon containing critical active site/substrate binding residues (exons 8 and 10), or for which another variant removing the exon is known to be pathogenic (exons 2 and 18).
Gene: GAA (HGNC:4065)
Evidence Code: PVS1 — Strong
Modification Type: Strength,Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




In frame loss of an exon which is part of the catalytic barrel domain and contains pathogenic/likely pathogenic nontruncating variants (exons 6 and 9).


Initiator codon variant.
Gene: GAA (HGNC:4065)
Evidence Code: PVS1 — Moderate
Modification Type: Strength,Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




Premature termination codon in the 3’ end of GAA (3’ to codon 916), not predicted to be detected by nonsense-mediated decay.


Predicted exon-skipping due to canonical splice variant or exon deletion resulting in an in frame deletion of <10% of the gene product (exons 17, 19, and 20).
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: PS1 — Strong
Modification Type: None
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: PS3 — Strong
Modification Type: None
Well-established in vitro or in vivo functional studies supportive of a damaging effect.




RT-PCR evidence of mis-splicing for non-canonical intronic variants with no evidence of normal splice products.
Gene: GAA (HGNC:4065)
Evidence Code: PS3 — Moderate
Modification Type: Strength,Disease-specific
Well-established in vitro or in vivo functional studies supportive of a damaging effect.




<5% wild type GAA activity when the variant is expressed in a heterologous cell type and evidence of abnormal GAA synthesis and/or processing.


RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.
Gene: GAA (HGNC:4065)
Evidence Code: PS3 — Supporting
Modification Type: Strength,Disease-specific
Well-established in vitro or in vivo functional studies supportive of a damaging effect.




<30% wild type GAA activity when the variant is expressed in a heterologous cell type.


RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: PM1 — Moderate
Modification Type: Disease-specific
Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.




Missense substitution or in frame deletion of residues important in the active site architecture and substrate binding of GAA:- D282, W376, D404, L405, I441, W481, W516, D518, M519, R600, W613, D616, W618, F649, L650, H674.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: PM2 — Moderate
Modification Type: Disease-specific
Low frequency in population databases.




Minor allele frequency <0.1% (0.001) in all continental populations with >2000 alleles in gnomAD.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: PM3 — Very Strong
Detected in trans with a pathogenic variant. Points-based system. See main specifications document.
Gene: GAA (HGNC:4065)
Evidence Code: PM3 — Strong
Detected in trans with a pathogenic variant. Points-based system. See main specifications document.
Gene: GAA (HGNC:4065)
Evidence Code: PM3 — Moderate
Modification Type: None
Detected in trans with a pathogenic variant. Points-based system. See main specifications document.
Gene: GAA (HGNC:4065)
Evidence Code: PM3 — Supporting
Modification Type: Strength
Detected in trans with a pathogenic variant. Points-based system. See main specifications document.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: PM4 — Moderate
Modification Type: None
Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants.




In frame deletion/insertions of two or more amino acids but less than one exon.
Gene: GAA (HGNC:4065)
Evidence Code: PM4 — Supporting
Modification Type: Strength
Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants.




In frame deletion/insertions of one amino acid.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: PM5 — Supporting
Modification Type: Strength
Missense change at an amino acid residue where a different missense change determined to be 'likely pathogenic' has been seen before.
Gene: GAA (HGNC:4065)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
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: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: PP3 — Supporting
Modification Type: Disease-specific
Multiple lines of computational evidence support a deleterious effect on the gene or gene product.




REVEL score >0.7 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).
Gene: GAA (HGNC:4065)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: GAA (HGNC:4065)
Evidence Code: PP4 — Moderate
Modification Type: Strength,Disease-specific
Phenotype specific for disease with single genetic etiology.




Points-based system. See main specifications document
Gene: GAA (HGNC:4065)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific
Phenotype specific for disease with single genetic etiology.




Points-based system. See main specifications document
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: GAA (HGNC:4065)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Common in population databases.




Highest minor allele frequency >0.01 (>1%) in any continental population in gnomAD with >2000 alleles.
Gene: GAA (HGNC:4065)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: GAA (HGNC:4065)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Allele frequency greater than expected for disease.




Highest minor allele frequency >0.005 (>0.5%) in any continental population in gnomAD with >2000 alleles.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: BS2 — Strong
Modification Type: None
Observed in the homozygous state in a healthy adult.




Homozygous individual of any age with normal GAA activity.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
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.






50% activity when the variant is expressed in a heterologous cell type, or >30% activity if there is also evidence of normal synthesis and processing.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: BP2 — Supporting
Modification Type: None
Observed in cis with a pathogenic variant.
Gene: GAA (HGNC:4065)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
Evidence Code: BP4 — Supporting
Modification Type: Disease-specific
Multiple lines of computational evidence suggest no impact on gene or gene product.




REVEL score <0.5 for missense variants.


In frame deletion or insertion predicted benign by PROVEAN, MutationTaster, and MutPred-InDel.


No predicted impact on splicing by SpliceAI (score <0.2)
Gene: GAA (HGNC:4065)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: GAA (HGNC:4065)
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: GAA (HGNC:4065)
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: GAA (HGNC:4065)
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.