owencqueen/cgbench_data huggingface dataset:
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: PVS1 — Very Strong
Modification Type: Gene-Specific,Strength
See HNF1A PVS1 decision tree.
Gene: HNF1A (HGNC:11621)
Evidence Code: PVS1 — Strong
Modification Type: Gene-Specific,Strength
See HNF1A PVS1 decision tree.
Gene: HNF1A (HGNC:11621)
Evidence Code: PVS1 — Supporting
Modification Type: Gene-Specific,Strength
Use HNF1A PVS1 decision tree.
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: PS1 — Strong
No change
Gene: HNF1A (HGNC:11621)
Evidence Code: PS1 — Supporting
Modification Type: Strength
PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: PS2 — Very Strong
Modification Type: Gene-specific,Strength
Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.
Gene: HNF1A (HGNC:11621)
Evidence Code: PS2 — Strong
Modification Type: Gene-specific,Strength
Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.
Gene: HNF1A (HGNC:11621)
Evidence Code: PS2 — Moderate
Modification Type: Gene-specific,Strength
Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.
Gene: HNF1A (HGNC:11621)
Evidence Code: PS2 — Supporting
Modification Type: Gene-specific,Strength
Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: PS3 — Strong
Modification Type: Gene-specific,Strength
Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.
Gene: HNF1A (HGNC:11621)
Evidence Code: PS3 — Moderate
Modification Type: Gene-specific,Strength
Applicable for variants with luciferase assay data (evidence of decreased transactivation (<=40% of wild type) by the Gloyn/Oxford group (Althari et al 2020 
https://pubmed.ncbi.nlm.nih.gov/32910913/
)
Gene: HNF1A (HGNC:11621)
Evidence Code: PS3 — Supporting
Modification Type: Gene-specific,Strength
See list of approved functional studies and guidelines for interpretation of data (below).
(1) Luciferase assays for transactivation - "Decreased function" is defined as activity less than 40% of wildtype. Assays should include controls for WT, T2DM-risk, and known MODY variants. For additional specifications and recommendations, please see the HNF1A rules.
(2) EMSA for DNA binding - "Decreased function" is defined as activity lesss than 405 of wildtype. We recommend that at least two of the following variants be used as positive controls for reduced DNA binding activity: c.335C>T (p.Pro112Leu), c.608G>A (p.Arg203His), c.787C>T (p.Arg263Cys) and c.686G>A (p.Arg229Gln) (PMID: 11162430, 12574234, 24915262). For additional specifications and recommendations, please see the HNF1A rules.
(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between experimental protocols. Altered protein expression can be indirectly captured through the read-out frame from transactivation assay, and reduced protein expression can provide an explanation for reduced transactivation. When exploring protein mis-localization, we recommend that the c.589_615del (p.Lys197_Lys205del) variant is included as a positive control for impaired nuclear localization (cytosolic retention).
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: PS4 — Strong
Modification Type: Gene-specific,Strength
Seven or more= Strong. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see below).
Gene: HNF1A (HGNC:11621)
Evidence Code: PS4 — Moderate
Modification Type: Gene-specific,Strength
4-6 unrelated occurrences = Moderate.
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: PM1 — Moderate
Modification Type: Gene-specific,Strength
This criterion can be used for variants in residues that directly bind DNA:   Gln130, Arg131, Glu132, His143, Leu144, Ser145, Gln146, His147, Leu148, Asn149, Lys155, Thr156, Gln157, Lys158, Arg203, Phe204, Lys205, Trp206, Arg263, Val264, Tyr265, Asn270, Arg271, Arg272, Lys273
Gene: HNF1A (HGNC:11621)
Evidence Code: PM1 — Supporting
Modification Type: Gene-specific,Strength
Use for defined regions in the DNA binding and dimerization domains. 




Dimerization: codons 1-32, NM_000545.8 


Subset of DNA binding domains: codons 107-174 and 201-280, NM_000545.8 
It can also be used for variants within certain transcription factor binding sites of the promoter.  


–c.-187 to c.-195 (AP1 binding site) 


–c.-209 to c.-227 (Overlapping HNF3 & NF-Y sites) 


–c.-238 to c.-259 (HNF1A binding site) 


–c.-276 to c.-288 (HNF4A binding site)
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: PM2 — Supporting
Modification Type: General recommendation,Gene-specific
Prevalence ≤ 1:50,000 (≤ 0.00002 or 0.002%) in gnomAD v2.1.1 European Non-Finnish population AND ≤ 1 copy in other founder and non-founder populations (would require ≤ 1/50,000 in non-European populations if/when they surpass 100,000 alleles).
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: PM4 — Moderate
Modification Type: Strength
For single amino acid deletions, use as supporting level of evidence.
Gene: HNF1A (HGNC:11621)
Evidence Code: PM4 — Supporting
Modification Type: Strength
For single amino acid deletions/insertions, use as supporting level of evidence
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: PM5 — Strong
Modification Type: Strength
Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue
Gene: HNF1A (HGNC:11621)
Evidence Code: PM5 — Moderate
Modification Type: Strength
The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.
Gene: HNF1A (HGNC:11621)
Evidence Code: PM5 — Supporting
Modification Type: Strength
Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.
Gene: HNF1A (HGNC:11621)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: PP1 — Strong
Modification Type: Gene-specific,Stength,General recommendation
Use thresholds suggested by Jarvik and Browning (PMID: 27236918)




Single Family : ≤ 1/32 (5 meioses) 




1 Family : ≤ 1/16 (4 meioses)
Gene: HNF1A (HGNC:11621)
Evidence Code: PP1 — Moderate
Modification Type: Gene-specific,Stength,General recommendation
Use thresholds suggested by Jarvik and Browning (PMID: 27236918)




Single Family : ≤ 1/16 (4 meioses)




1 Family : ≤ 1/8 (3 meioses)
Gene: HNF1A (HGNC:11621)
Evidence Code: PP1 — Supporting
Modification Type: Gene-specific,Stength,General recommendation
Use thresholds suggested by Jarvik and Browning (PMID: 27236918)




Single Family : ≤ 1/8 (3 meioses)          




1 Family : ≤ ¼ (2 meioses)
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: PP3 — Supporting
Modification Type: General recommendation
Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).
Gene: HNF1A (HGNC:11621)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: HNF1A (HGNC:11621)
Evidence Code: PP4 — Moderate
Modification Type: Gene-specific,strength
MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
https://www.diabetesgenes.org/mody-probability-calculator/
) AND negative HNF4A testing AND presence of at least one additional feature characteristic of HNF1A-MODY:




Antibody negative and/or persistent C-peptide after five years post- T1DM diagnosis


Response to low-dose SU (extreme response- hypoglycemia)


Low hsCRP in patient with clinical diagnosis of T2DM


Biochemical/Molecular phenotypic evidence from patient cell lines


Hepatocellular adenomas
Gene: HNF1A (HGNC:11621)
Evidence Code: PP4 — Supporting
Modification Type: Gene-specific,strength
MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
https://www.diabetesgenes.org/mody-probability-calculator/
) AND negative HNF4A testing
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: HNF1A (HGNC:11621)
Evidence Code: BA1 — Stand Alone
Modification Type: Gene-specific
MAF ≥ 1:10,000 (≥ 0.01% or 0.0001) in gnomAD Popmax Filtering AF.
Gene: HNF1A (HGNC:11621)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: HNF1A (HGNC:11621)
Evidence Code: BS1 — Strong
Modification Type: Gene-specific
MAF ≥ 1:30,000 (≥0.0033% or 0.000033) in gnomAD Popmax Filtering AF.
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: BS2 — Strong
Modification Type: Gene-specific
Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: BS3 — Strong
Modification Type: Gene-specific,strength
Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.
Gene: HNF1A (HGNC:11621)
Evidence Code: BS3 — Supporting
Modification Type: Gene-specific,strength
See HNF1A rules for full list of approved functional studies and guidelines for interpretation of data. 
(1) Luciferase assays for transactivation - "No functional impact" is defined as ≥ 75% activity of wildtype
(2) EMSA for DNA binding - "No functional impact" is defined as ≥ 75% activity of wildtype.
(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation.
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: BS4 — Strong
Modification Type: Gene-specific
Applicable to family members without variant who have MPC score >50% (i.e., genotype negative, phenotype positive).
Gene: HNF1A (HGNC:11621)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: BP2 — Supporting
Modification Type: General recommendation
Also applicable when in cis or trans with a likely pathogenic variant.
Gene: HNF1A (HGNC:11621)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: BP4 — Supporting
Modification Type: General recommendation
Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).
Gene: HNF1A (HGNC:11621)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: HNF1A (HGNC:11621)
Evidence Code: BP5 — Supporting
Modification Type: General recommendation
A variant in other monogenic diabetes gene is P/LP.
Gene: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
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: HNF1A (HGNC:11621)
Evidence Code: BP7 — Supporting
Use with no specifications.