Criteria Specification Registry

Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.

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Criteria Specification

ClinGen FBN1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Description : This version specified for the following genes: FBN1

Version : 1.0.0

PDF

FBN1 VCEP

Released

1/5/2022

06:00:00

Rules for FBN1

Gene: FBN1 (HGNC:3603) HGNC Name: fibrillin 1 Transcripts: NM_000138 Disease: Marfan syndrome (MONDO:0007947)

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong 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. Modification Type: Disease-specific Strong 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. Modification Type: Strength Moderate Initiation codon variant with 1 or more pathogenic variant(s) upstream of closest potential in-frame start codon. Modification Type: Strength Supporting Instructions: Follow the adapted flowchart. There is only 1 relevant transcript for FBN1 (NM_000138). The C-terminal region is proven to be critical to protein function (multiple LP/P variants identified in this region). PP3 cannot be applied if using the PVS1criterion for splice site variants in position +/- ½. Not Applicable
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong 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. Modification Type: None Moderate Supporting Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Four points Modification Type: Strength Strong Two-three points Modification Type: Disease-specific Moderate One point Modification Type: Strength Supporting 0.5 points Modification Type: Strength Instructions: Use the SVI WG point-based system https://clinicalgenome.org/working-groups/sequencevariant- interpretation/ The expert panel provided definitions for: ‘highly specific phenotype’: TAAD + ectopia lentis (mainly caused by variants in FBN1). ‘consistent phenotype:’ TAAD + systemic score ≥7 (can be caused by variants in few other HTAD genes). ‘consistent but genetic heterogeneity’:(isolated) TAAD, isolated ectopia lentis and in case of a child (age <20yrs) systemic score≥ 7 in whom TAAD is progressive and can be developed later in life. The EP recommends that the parents had a full clinical work-up and an echocardiogram to exclude MFS/HTAAD. Not Applicable
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Follow the ‘Funtional Assay SVI Documentation’ Modification Type: Disease-specific Moderate Follow the ‘Funtional Assay SVI Documentation’ Modification Type: Strength Supporting Use the ‘Funtional Assay SVI Documentation’. Modification Type: Strength Instructions: 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. Not Applicable
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong If ≥ 4 points. Modification Type: Disease-specific Moderate If 2-3.5 points. Modification Type: Strength Supporting If 1-1.5 points. Modification Type: Strength Instructions: Each additional proband meeting Ghent criteria or having ectopia lentis may receive 1 point while those having only thoracic aortic disease or high systemic score or those for which the phenotype is not described in the literature will receive 0.5 points. * Caveat: BA1/BS1 should not be met. Not Applicable
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Cys residues in cbEGF-like domains Add caveat: PM5/PS1 should not be used when this argument applies. Modification Type: Strength Moderate 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. Modification Type: Disease-specific Supporting Not Applicable
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate Supporting 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. Modification Type: Strength Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Stand Alone Very Strong Strong Moderate Add caveat: cannot be applied simultaneously with PVS1 (at any strength level) Modification Type: None Supporting Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate 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. Modification Type: None Supporting Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. Stand Alone Very Strong 4 points Modification Type: Strength Strong 2-3 points. Modification Type: Disease-specific Moderate 1 point. Modification Type: Disease-specific Supporting 0.5 points. Modification Type: Strength Instructions: Use the SVI WG point-based system https://clinicalgenome.org/working-groups/sequencevariant- interpretation/ The expert panel provided definitions for: ‘highly specific phenotype’: TAAD + ectopia lentis (mainly caused by variants in FBN1). ‘consistent phenotype:’ TAAD + systemic score ≥7 (can be caused by variants in few other HTAD genes). ‘consistent but genetic heterogeneity’:(isolated) TAAD, isolated ectopia lentis and in case of a child (age <20yrs) systemic score≥ 7 in whom TAAD is progressive and can be developed later in life. The EP recommends that the parents had a full clinical work-up and an echocardiogram to exclude MFS/HTAAD. Not Applicable
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong ≥5 affected individuals. Modification Type: Strength Moderate 4 affected individuals. Modification Type: Strength Supporting 2-3 affected individuals. Modification Type: Disease-specific Instructions: Only count affected individuals from the same family (minus proband) that carry the variant or obligate carriers known with the disease. The EP will not specifically define “affected”, “clinical examination” or cut-offs for aortic Z-scores. These are left to the discretion of the referring physicians. Not Applicable
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate Supporting Add caveat: if this argument is used pro-pathogenicity, there must be other arguments supporting pathogenicity, and no arguments supporting a benign assertion. Modification Type: None Not Applicable
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate Supporting 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. Modification Type: Disease-specific Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Stand Alone Very Strong Strong Moderate Supporting Use if patient fulfils revised Ghent criteria. Can be used if any of the family members have a highly specific phenotype. Modification Type: Disease-specific Not Applicable
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. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone 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. Modification Type: Disease-specific Very Strong Strong Moderate Supporting Not Applicable
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong 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. Modification Type: Disease-specific Moderate Supporting Not Applicable
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong 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. Modification Type: None Moderate Supporting Not Applicable
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Caution is warranted when the phenotype is not highly specific. Lack of segregation should then be clear in >1 affected family member. Modification Type: None Moderate Supporting Not Applicable
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate Supporting 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. Modification Type: Disease-specific Not Applicable
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate Supporting 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. Modification Type: Disease-specific Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong Moderate Supporting Variant found in a case with an alternate molecular basis for disease. Modification Type: None Not Applicable
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. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Stand Alone Very Strong Strong Moderate Supporting 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. Modification Type: None Not Applicable