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 Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0

Description : Rule specifications for antithrombin deficiency.

Version : 1.0.0 Release Notes :

All requested edits were made in this document and in the VCI, with exception of one. We would like the p.Cys29= variant to remain a VUS since there is only one benign code assigned. The point counting system is currently only being applied when conflicting rules codes are applied.

Thrombosis VCEP

Released

7/17/2023

13:46:49

Rules for SERPINC1

Gene: SERPINC1 (HGNC:775) HGNC Name: serpin family C member 1 Transcripts: NM_000488.4 Disease: antithrombin III deficiency (MONDO:0013144) Mode of Inheritance: Autosomal dominant inheritance

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 Use decision tree as per SVI WG with specified “regions critical to protein function”. Modification Type: Gene-specific Strong Use decision tree as per SVI WG with specified “regions critical to protein function”. Modification Type: Gene-specific Moderate Use decision tree as per SVI WG with specified “regions critical to protein function”. Modification Type: Gene-specific Supporting Use decision tree as per SVI WG with specified “regions critical to protein function”. Modification Type: Gene-specific 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 Use with no specification except comparison variant must be classified as pathogenic using SERPINC1 rule specifications from the Thrombosis VCEP. Modification Type: Gene-specific Moderate Use with no specification except comparison variant must be classified as likely pathogenic using SERPINC1 rule specifications from the Thrombosis VCEP. Modification Type: Gene-specific Supporting Instructions: Use caution not to compare variants being curated to variants that are potential cryptic slice sites. 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 Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 4 points. Modification Type: Disease-specific Strong Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 2 points. Modification Type: Disease-specific Moderate Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 1 point. Modification Type: Disease-specific Supporting Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 0.5 point. Modification Type: Disease-specific Instructions: Any proband must meet the PP4 defined antithrombin deficiency laboratory phenotype (see PP4/PS4 description below). 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 Moderate Supporting See attached spreadsheet for list of approved assays to use for this rule code. Below is a general description of assays that can be used: - In vitro functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal activity levels: Antithrombin activity levels measured by FXa inhibition activity assay Antithrombin activity levels measured by thrombin inhibition activity assay OR - In vitro functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal antigen levels: Antithrombin antigen levels measured by ELISA Immunofluorescence assay – intracellular retention and secretion defects OR - In vivo studies demonstrating rescue of antithrombin levels would be considered, but no studies are known to be available at this time. Modification Type: Disease-specific Instructions: Model organism do not tend to recapitulate the phenotype of interest and are not used for curation. 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 Appropriate to use code when there 8 or more proband points that meet the defined antithrombin deficiency laboratory phenotype. Modification Type: Disease-specific Strong Appropriate to use code when there 4-7 proband points that meet the defined antithrombin deficiency laboratory phenotype. Modification Type: Disease-specific Moderate Appropriate to use code when there 2-3 proband points that meet the defined antithrombin deficiency laboratory phenotype. Modification Type: Disease-specific Supporting Appropriate to use code when there is 1 proband point that meets the defined antithrombin deficiency laboratory phenotype. Modification Type: Disease-specific Instructions: This code requires the use of proband points. Please see attached guidance on tallying proband points for this phenotype. Do not apply this code for variants that meet BS1 or BA1 criteria. Do not count proband used for PP4 in this code's proband count. 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 Moderate This code is applicable for variants disrupting cystine residues involved in disulfide bridges (Cys40, Cys53, Cys127, Cys160, Cys279, Cys462)¹, variants that would impact heparin binding site residues (Ile39, Arg56, Pro73, Arg79) and variants involving reactive site residues (Ala414 and Ala416)². Modification Type: Gene-specific Supporting Not Applicable Comments: Rule does not apply due to benign variation being present throughout the gene and no known hotspots.
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 Use code for variants with a popmax MAF of <0.00002 in gnomAD. Modification Type: Disease-specific,Gene-specific 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 Comments: Variants in this gene are being curated as a dominant condition, so this rule code does not apply.
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 No specification 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 Use code when previously reported variant reaches a pathogenic classification using the SERPINC1 rule specifications from the Thrombosis VCEP. Modification Type: General recommendation Supporting Use code when previously reported variant reaches a likely pathogenic classification using the SERPINC1 rule specifications from the Thrombosis VCEP. Modification Type: General recommendation Instructions: Use caution not to compare variants being curated to variants that are potential cryptic slice sites. 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 Strong Moderate Supporting Not Applicable Comments: Use the PS2 code in lieu of using this code for de novo variants.
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 Appropriate to use there are 7 or more meioses across more than one family. Modification Type: Disease-specific Moderate Appropriate to use there are 4-6 meioses across one or more families. Modification Type: Disease-specific Supporting Appropriate to use when there are 2-3 meioses across one or more families. Modification Type: Disease-specific 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 Not Applicable Comments: Not applicable due to presence of benign variation throughout the SERPINC1 gene.
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 Appropriate to use for missense variants that have a REVEL score of greater or equal to 0.6. For potential splicing variants, use of 2 independent in silico splicing tools must predict a damaging impact. Modification Type: Gene-specific Instructions: Recommended splicing prediction tools are VarSEAK and SpliceAI. Recommended score for SpliceAI is greater or equal to 0.5. 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 Proband must have an antithrombin activity level of < 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range). confirmed on repeated independent samples. An abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function may be used in lieu of low activity levels, which is typically caused by type II variants. Modification Type: Disease-specific Instructions: Please see attached guidance regarding the use of PP4/PS4 rule codes to properly assess eligibility. Do not apply this code for variants that meet BS1 or BA1 criteria. Do not count the proband used for the PP4 code for the PS4 code's proband count. 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 Appropriate to use for variants with a popmax MAF of greater than or equal to 0.002 in gnomAD. Modification Type: Disease-specific,Gene-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 Appropriate to use for variants with a Popmax MAF of >0.0002 in gnomAD. Modification Type: Disease-specific,Gene-specific Moderate Supporting Instructions: Common founder SERPINC1 variants are excluded from eligibility of the BS1 code. The list of variants will likely grow over time, but currently consists of the SERPINC1 c.218C>T; p.Pro73Leu (PMID:23910795), SERPINC1 c.236G>A; p.Arg79His (AT Padua), SERPINC1 c.439A>G; p.Thr147Ala (PMID:32920809) and SERPINC1 c.1246G>T ; SERPINC1 p.Ala416Ser (AT Cambridge II); SERPINC1 p.Leu131Phe (PMID:26748602) variants. 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 This evidence code is available when the variant is identified in 2 or more heterozygotes or 1 or more homozygotes with normal antithrombin levels [> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)]. Modification Type: Disease-specific Moderate Supporting This evidence code is available when the variant is identified in 1 heterozygote with normal antithrombin levels [> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)]. Modification Type: Disease-specific Not Applicable Comments: Not applicable due to the incomplete penetrance seen in VWD.
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 Moderate Supporting Not Applicable Comments: There are no available assays or model organisms that can recapitulate disease, and in vitro studies cannot dependably rule out pathogenicity.
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 Appropriate to use when the variant is found not to segregate in a minimum of four relatives with abnormal antithrombin activity levels [< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)] within the same family, OR the variant does not segregate in 2 or more families. Non-segregation defined by having abnormal antithrombin activity levels without SERPINC1 variant of interest. Modification Type: Disease-specific Moderate Supporting Appropriate to use when the variant is found not to segregate in a minimum of two relatives with abnormal antithrombin activity levels [< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)] within the same family. Modification Type: Disease-specific 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 Comments: This rule code does not apply to the SERPINC1 gene, as missense and truncating variants account for disease.
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 This rule can be applied when a SERPINC1 variant is in cis with another pathogenic SERPINC1 variant. The pathogenic variant must be evaluated using ClinGen SERPINC1 specified rules. This rule cannot be applied to a variant in trans with a pathogenic variant, as this scenario could reasonably occur and increase the risk of venous thrombosis. Modification Type: Disease-specific Not Applicable Comments: Do not use as individuals can be homozygous for SERPINC1 variants.
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 Comments: There are no known repetitive regions in the SERPINC1 gene without a known function.
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 Use this code for missense variants with a REVEL score of < 0.30 and no evidence of a potential splicing effect using VarSEAK and Splice AI prediction tools, or for non-canonical intronic variants with no evidence of a potential splicing effect using VarSEAK and Splice AI prediction tools. Modification Type: Gene-specific Not Applicable Comments: Not using at this time but will note CADD and SpliceAI scores and consider use during pilot testing.
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 Not Applicable Comments: This rule code is not recommended for use at this time. There are other genes that can be associated with decreased antithrombin activity levels, such as genes associated with the congenital disorders of glycosylation.
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 Use tools VarSEAK and Splice AI to rule out a predicted splicing effect. Evolutionary conservation is defined as a PhyloP < 0.1 OR the reference nucleotide is present in 3 mammals or 1 primate. Modification Type: General recommendation Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND ≥ 1 Strong (PS1, PS2, PS4, PP1_Strong)

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND ≥ 2 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate)

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND 1 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate) AND 1 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

≥ 2 Strong (PS1, PS2, PS4, PP1_Strong)

1 Strong (PS1, PS2, PS4, PP1_Strong) AND ≥ 3 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate)

1 Strong (PS1, PS2, PS4, PP1_Strong) AND 2 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Strong (PS1, PS2, PS4, PP1_Strong) AND 1 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate) AND ≥ 4 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

Likely Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND 1 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate)

Benign

≥ 2 Strong (BS1, BS2, BS4)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BS4) AND 1 Supporting (BS2_Supporting, BS4_Supporting, BP2, BP4, BP7)

≥ 2 Supporting (BS2_Supporting, BS4_Supporting, BP2, BP4, BP7)

Files & Images

De novo rule guidance :

Phenotype rules (PS4/PP4) guidance :

SERPINC1 functional assay list :

SERPINC1 Rule code combination rules: Use these rules when there are variants with benign and pathogenic rule codes applied.

References

1. Kottke-Marchant K Duncan A Antithrombin deficiency: issues in laboratory diagnosis. Arch Pathol Lab Med (2002) 126 (11) p. 1326-36. 10.5858/2002-126-1326-AD 12421140

2. Perry DJ Carrell RW CpG dinucleotides are "hotspots" for mutation in the antithrombin III gene. Twelve variants identified using the polymerase chain reaction. Mol Biol Med (1989) 6 (3) p. 239-43. 2615648

3. Orlando C de la Morena-Barrio B et al. Antithrombin p.Thr147Ala: The First Founder Mutation in People of African Origin Responsible for Inherited Antithrombin Deficiency. Thromb Haemost (2021) 121 (2) p. 182-191. 10.1055/s-0040-1716531 32920809