owencqueen/cgbench_data huggingface dataset:
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: PVS1 — Very Strong
Modification Type: Disease-specific
Nonsense/frameshift variants predicted to undergo NMD (not affecting last exon or 55 last nt of penultimate exon).


1,2 splice site variants leading to exon skipping or use of a cryptic splice site disrupting the reading frame and predicted to undergo NMD.


Full gene deletion.


Single to multi-exon deletion disrupting the reading frame and predicted to undergo NMD.


Duplication (>=1 exon in size and completely contained within gene) proven in tandem and disrupting the reading frame and predicted to undergo NMD.
Gene: FBN1 (HGNC:3603)
Evidence Code: PVS1 — Strong
Modification Type: Strength
Nonsense/frameshift variants predicted to escape NMD (affecting last exon, last 55nt of the penultimate exon).


1,2 splice site variants leading to exon skipping or use of a cryptic splice site disrupting the reading frame and predicted to escape NMD.


1,2 splice site variants leading to exon skipping or use of a cryptic splice site but preserving the reading frame.


Single to multi-exon deletion disrupting the reading frame and predicted to escape NMD.


Single to multi-exon deletion preserving the reading frame.


Duplication (>=1 exon in size and completely contained within gene) presumed in tandem and presumably disrupting the reading frame and predicted to escape NMD.
Gene: FBN1 (HGNC:3603)
Evidence Code: PVS1 — Moderate
Modification Type: Strength
Initiation codon variant with 1 or more pathogenic variant(s) upstream of closest potential in-frame start codon.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: PS1 — Strong
Modification Type: None
Beware of changes that impact splicing rather than the amino acid. Splicing predictions should remain the same for WT and mutant alleles.


Original variant should be pathogenic according to the (modified) ACMG guidelines for variant classification.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: PS2 — Very Strong
Modification Type: Strength
Four points
Gene: FBN1 (HGNC:3603)
Evidence Code: PS2 — Strong
Modification Type: Disease-specific
Two-three points
Gene: FBN1 (HGNC:3603)
Evidence Code: PS2 — Moderate
Modification Type: Strength
One point
Gene: FBN1 (HGNC:3603)
Evidence Code: PS2 — Supporting
Modification Type: Strength
0.5 points
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific
Follow the ‘Funtional Assay SVI Documentation’
Gene: FBN1 (HGNC:3603)
Evidence Code: PS3 — Moderate
Modification Type: Strength
Follow the ‘Funtional Assay SVI Documentation’
Gene: FBN1 (HGNC:3603)
Evidence Code: PS3 — Supporting
Modification Type: Strength
Use the ‘Funtional Assay SVI Documentation’.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: PS4 — Strong
Modification Type: Disease-specific
If ≥ 4 points.
Gene: FBN1 (HGNC:3603)
Evidence Code: PS4 — Moderate
Modification Type: Strength
If 2-3.5 points.
Gene: FBN1 (HGNC:3603)
Evidence Code: PS4 — Supporting
Modification Type: Strength
If 1-1.5 points.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: PM1 — Strong
Modification Type: Strength
Cys residues in cbEGF-like domains


Add caveat: PM5/PS1 should not be used when this argument applies.
Gene: FBN1 (HGNC:3603)
Evidence Code: PM1 — Moderate
Modification Type: Disease-specific
Cys in EGF-like domain, Cys in TB domain, Cys in hybrid domain, (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) substitution in cbEGF-like domain, invariant calcium-binding or hydroxylation residue in cbEGF-like domain, critical Gly between Cys2-Cys3 in cbEGF-like domain, Gly between Cys3-Cys4 if there is an upstream cbEGF domain, Cys-creating variants.


Add caveat: N to S substitution in the second N of de consensus sequence and G to A might be tolerated, PM1 should not be used in these cases.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: PM2 — Supporting
Modification Type: Strength
Threshold: <5.0E-6 (<0.0005%).


Use the highest ethnic population allele frequency.


Caveat: PVS1 + PM2_Supportive may reach Likely Pathogenic.


Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.


Minimum amount of studied alleles should be 2000.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: PM4 — Moderate
Modification Type: None
Add caveat: cannot be applied simultaneously with PVS1 (at any strength level)
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: PM5 — Moderate
Modification Type: None
Add caveat: Use argument with caution when the original missense variant created a cysteine especially in a cbEGFlike domain (cfr PM1_strong) as this may increase the
pathogenicity level of this variant improperly.


Add caveat: original variant should be pathogenic according to the (modified) ACMG guidelines for variant classification.
Gene: FBN1 (HGNC:3603)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: FBN1 (HGNC:3603)
Evidence Code: PM6 — Very Strong
Modification Type: Strength
4 points
Gene: FBN1 (HGNC:3603)
Evidence Code: PM6 — Strong
Modification Type: Disease-specific
2-3 points.
Gene: FBN1 (HGNC:3603)
Evidence Code: PM6 — Moderate
Modification Type: Disease-specific
1 point.
Gene: FBN1 (HGNC:3603)
Evidence Code: PM6 — Supporting
Modification Type: Strength
0.5 points.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: PP1 — Strong
Modification Type: Strength
≥5 affected individuals.
Gene: FBN1 (HGNC:3603)
Evidence Code: PP1 — Moderate
Modification Type: Strength
4 affected individuals.
Gene: FBN1 (HGNC:3603)
Evidence Code: PP1 — Supporting
Modification Type: Disease-specific
2-3 affected individuals.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: PP2 — Supporting
Modification Type: None
Add caveat: if this argument is used pro-pathogenicity, there must be other arguments supporting pathogenicity, and no arguments supporting a benign assertion.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: PP3 — Supporting
Modification Type: Disease-specific
Recommended prediction program for missense variants: REVEL. Use 0.75 as a discriminatory cut-off value.


Recommended prediction programs for splice variants: GeneSplicer, MaxEntscan, and NNSPLICE. The outcome of all 3 prediction programs need to be in concordance.
Gene: FBN1 (HGNC:3603)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: FBN1 (HGNC:3603)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific
Use if patient fulfils revised Ghent criteria.


Can be used if any of the family members have a highly specific phenotype.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: FBN1 (HGNC:3603)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Allele frequency above 0.1% in ExAc and gnomAD




Use the ethnic population with the highest allele frequency.


Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.


Minimum amount of studied alleles should be 2000.
Gene: FBN1 (HGNC:3603)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: FBN1 (HGNC:3603)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Allele frequency greater than expected for disease (>0.005%).




Use the ethnic population with the highest allele frequency.


Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.


Minimum amount of studied alleles should be 2000.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: BS3 — Strong
Modification Type: None
Use the ‘Funtional Assay SVI Documentation’ (
https://clinicalgenome.org/workinggroups/sequence-variant-interpretation/
).
For step 2 assessment.




Functional studies deemed appropriate:


cDNA analyses showing altered FBN1 sequence.


Functional studies showing altered FBN1 protein or RNA expression, proteolysis, folding, assembly, trafficking, secretion, Ca2+ binding, matrix deposition (cfr Dave Hollister assay), microfibril fragmentation/catabolism in an in vitro engineered system.


Functional studies NOT deemed appropriate: non-specific altered TGF-beta signaling or histological hallmarks of medial degeneration, which are associated with many other types of variants in genes that are associated with MFS or HTAAD in general.
For step 3 assessment: Studies should be performed in the presence of NMD inhibitor.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: BS4 — Strong
Modification Type: None
Caution is warranted when the phenotype is not highly specific. Lack of segregation should then be clear in >1 affected family member.
Gene: FBN1 (HGNC:3603)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: BP2 — Supporting
Modification Type: Disease-specific
Observed in trans in multiple cases (+2) with co-occuring pathogenic variants and phenotype is not more severe than when seen in isolation.


Observed in cis with a pathogenic variant, if the pathogenic variant has been seen in isolation in a patient with the disease phenotype.
Gene: FBN1 (HGNC:3603)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
Evidence Code: BP4 — Supporting
Modification Type: Disease-specific
Recommended prediction program for missense variants: REVEL. Use 0.326 as a discriminatory cut-off value.


Recommended prediction programs for splice variants: GeneSplicer, MaxEntscan, and NNSPLICE. The outcome of all 3 prediction programs need to be in concordance.
Gene: FBN1 (HGNC:3603)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: FBN1 (HGNC:3603)
Evidence Code: BP5 — Supporting
Modification Type: None
Variant found in a case with an alternate molecular basis for disease.
Gene: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
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: FBN1 (HGNC:3603)
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.
BP7 applicable as described.