owencqueen/cgbench_data huggingface dataset:
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: PVS1 — Very Strong
Modification Type: Disease-specific,Strength
See PVS1 flow diagram (Figure 1).
Gene: LDLR (HGNC:6547)
Evidence Code: PVS1 — Strong
Modification Type: Disease-specific,Strength
See PVS1 flow diagram (Figure 1).
Gene: LDLR (HGNC:6547)
Evidence Code: PVS1 — Moderate
Modification Type: Disease-specific,Strength
See PVS1 flow diagram (Figure 1).
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: PS1 — Strong
Modification Type: Clarification
Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts the same amino acid change.
Caveat: there is no in silico predicted splicing impact for either variant.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: PS2 — Strong
Modification Type: Clarification
Variant is de novo in a patient with the disease and no family history. Follow SVI guidance for de novo occurrences: 
https://clinicalgenome.org/working-groups/sequence-variant-interpretation/
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific,Strength
Variant meets Level 1 pathogenic functional study criteria. See Table 3.
(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with noendogenous LDLR) transfected with mutant plasmid. Assay result of <70% ofwild-type activity in either expression/biosynthesis, binding OR internalization.
Gene: LDLR (HGNC:6547)
Evidence Code: PS3 — Moderate
Modification Type: Disease-specific,Strength
Variant meets Level 2 pathogenic functional study criteria. See Table 3.
(1) Study of a) only part of the LDLR cycle following Level 1 methodology, or b) whole or part of the LDLR cycle in true homozygous patient cells. A variant with assay results of <70% of wild type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.
(2) RNA studies, using RNA extracted from heterozygous or true homozygous patient cells, where aberrant transcript is confirmed by sequencing and is quantified as >25% of total transcript from heterozygous cells or 50% of total transcript from homozygous cells.
(3) Variants with two or more Level 3 functional studies (must be different assays); or any Level 3 functional study #1-4 performed by two or more independent labs with concordant results.
Gene: LDLR (HGNC:6547)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific,Strength
Variant meets Level 3 pathogenic functional study criteria. See Table 3.
 (1) Study of LDLR cycle (whole or part) in heterozygous patient cells, with assay results of <85% of wild-type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.
 (2) Luciferase studies with transcription levels of <50% compared to wild-type (applicable to 5’UTR/promoter variants).
 (3) Minigene splicing assays with <10% wild-type transcript present where anaberrant transcript from the candidate variant is confirmed by sequencing.
 (4) High-throughput assays, which include alternative microscopy assays (e.g.,Thormaehlen et al., 2015), Multiplex Assays of Variant Effect (MAVE) (e.g.,Weile & Roth, 2018) and deep mutational scanning assays, can be considered here, only if assay has been validated with a minimum of four pathogenic and four benign variant controls in LDLR. Note: % activity thresholds will be defined by the FH VCEP as more data becomes available.
 (5) RNA studies, using RNA extracted from heterozygous or homozygous patient cells, with aberrant transcript confirmed by sequencing (but without transcript quantification).
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: PS4 — Strong
Modification Type: Disease-specific,Strength
Variant is found in ≥10 unrelated FH cases (FH diagnosis met by validated clinical criteria).
Caveat: variant must also meet PM2
Gene: LDLR (HGNC:6547)
Evidence Code: PS4 — Moderate
Modification Type: Disease-specific,Strength
Variant is found in 6-9 unrelated FH cases (FH diagnosis made by validated clinical criteria).
Caveat: variant must also meet PM2.
Gene: LDLR (HGNC:6547)
Evidence Code: PS4 — Supporting
Modification Type: Disease-specific,Strength
Variant is found in 2-5 unrelated FH cases (FH diagnosis made by validated clinical criteria).
Caveat: variant must also meet PM2.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: PM1 — Moderate
Modification Type: Disease-specific
Missense variant located in exon 4, or a missense change in one of 60 highly conserved cysteine residues (listed in Supp. Table 4). Caveat: variant must also meet PM2.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: PM2 — Moderate
Modification Type: Disease-specific
Variant has a PopMax MAF ≤0.0002 (0.02%) in gnomAD. Consider exceptions for known founder variants.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: PM3 — Moderate
Modification Type: Disease-specific
This criterion can be used for a candidate LDLR variant observed in an individual with a homozygous FH phenotype when there is only one other pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9. Caveat: variant must also meet PM2.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: PM4 — Moderate
Modification Type: Disease-specific
In-frame deletion/insertions smaller than one whole exon, or in-frame whole-exon duplications not considered in any PVS1 criteria.
Caveat: variant must also meet PM2.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: PM5 — Strong
Modification Type: Strength
Missense variant at a codon with ≥2 missense variants classified pathogenic (by these guidelines), and predicts a different amino acid change.
Gene: LDLR (HGNC:6547)
Evidence Code: PM5 — Moderate
Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts a different amino acid change.
Gene: LDLR (HGNC:6547)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: LDLR (HGNC:6547)
Evidence Code: PM6 — Moderate
Modification Type: Clarification
See PS2 above.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: PP1 — Strong
Modification Type: Disease-specific,Strength
Variant segregates with phenotype in ≥6 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant.
Gene: LDLR (HGNC:6547)
Evidence Code: PP1 — Moderate
Modification Type: Disease-specific,Strength
Variant segregates with phenotype in 4-5 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant.
Gene: LDLR (HGNC:6547)
Evidence Code: PP1 — Supporting
Modification Type: Disease-specific,Strength
Variant segregates with phenotype in 2-3 informative meioses in ≥1 family. Must include ≥1 affected relative (LDL-C >75th centile) with the variant.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: PP3 — Supporting
Modification Type: Disease-specific
REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
Gene: LDLR (HGNC:6547)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: LDLR (HGNC:6547)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific
Any LDLR variant identified in an FH patient [diagnosis based on validated clinical criteria, e.g. Dutch Lipid Clinic Network (≥6), Simon Broome possible/definite), MEDPED], after alternative causes of high cholesterol are excluded.
Caveat: variant must also meet PM2.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: LDLR (HGNC:6547)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Variant has a PopMax FAF ≥0.005 (0.5%) in gnomAD.
Gene: LDLR (HGNC:6547)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: LDLR (HGNC:6547)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Variant has a PopMax FAF ≥0.002 (0.2%) in gnomAD.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: BS2 — Strong
Modification Type: Disease-specific
Variant is identified in ≥3 heterozygous or ≥1 homozygous well-phenotyped, untreated, normolipidemic adults (unrelated).
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: BS3 — Strong
Modification Type: Disease-specific,Strength
Variant meets Level 1 benign functional study criteria. See Table 3.
(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with no endogenous LDLR) transfected with mutant plasmid. Assay result of >90% of wild-type activity in expression/biosynthesis, binding AND internalization.
Note: studies of only part of the LDLR cycle are not eligible for BS3 or BS3_Supporting.
Gene: LDLR (HGNC:6547)
Evidence Code: BS3 — Supporting
Modification Type: Disease-specific,Strength
Variant meets Level 3 benign functional study criteria. See Table 3.
(1) Study of whole LDLR cycle in a) true homozygous patient cells, with assay result of >90% of wild-type activity in biosynthesis, binding AND internalization; or in b) heterozygous patient cells with assay result of >95% of wild-type activity in biosynthesis, binding AND internalization.
(2) Luciferase studies with transcription levels of >90% when compared to wild-type (applicable to 5’UTR/promoter variants).
(3) RNA studies, using RNA extracted from heterozygous or homozygous patientcells, with a) aberrant transcripts quantification, where aberrant transcript is<10% of total transcript OR b) without transcript quantification where noaberrant transcript is confirmed by sequencing.
(4) Minigene splicing assay where only wild-type transcript is present and confirmed by sequencing.
(5) High-throughput assays as defined above; only applicable when assay canindicate the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding AND internalization) is unaffected.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: BS4 — Strong
Modification Type: Disease-specific
Lack of segregation in ≥2 index case families (unrelated), when data is available for ≥2 informative meioses in each family.
Caveat: must be ≥1 unaffected relative (LDL-C <50th centile) who is positive for the variant.
Gene: LDLR (HGNC:6547)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: BP2 — Supporting
Modification Type: Disease-specific
If a FH patient with a heterozygous phenotype has a pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9, BP2 is applicable to any additional LDLR variants.
Gene: LDLR (HGNC:6547)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: BP4 — Supporting
Modification Type: Disease-specific
REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
Gene: LDLR (HGNC:6547)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
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: LDLR (HGNC:6547)
Evidence Code: BP7 — Supporting
Modification Type: Disease-specific
Variant is synonymous.
Caveat: variant must also meet BP4 (i.e. no predicted impact on splicing).