Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_001386306.1:c.936A>G

CA421942771

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5a6d0cad-7f21-4636-99e2-f1d780c416d0

HGVS expressions

NM_001386306.1:c.936A>G

NC_000001.11:g.173909553T>C

CM000663.2:g.173909553T>C

NC_000001.10:g.173878691T>C

CM000663.1:g.173878691T>C

NC_000001.9:g.172145314T>C

NG_012462.1:g.12826A>G

ENST00000367698.4:c.1152A>G

ENST00000367698.3:c.1152A>G

ENST00000617423.4:c.560-2060A>G

NM_000488.3:c.1152A>G

NM_001365052.1:c.1008A>G

NM_000488.4:c.1152A>G

NM_001365052.2:c.1008A>G

NM_001386302.1:c.1275A>G

NM_001386303.1:c.1233A>G

NM_001386304.1:c.1131A>G

NM_001386305.1:c.1095A>G

Uncertain Significance

PP4 PP3 PS4_Moderate PM2_Supporting

Evidence Links 0

Expert Panel

Thrombosis VCEP

Criteria Specification Information

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Thrombosis VCEP

The c.1152A>G (NM_000488.3) variant in SERPINC1 is a synonymous variant that is not predicted to cause a substitution (p.Pro384=). The variant is absent from gnomAD v2.1.1 and v3.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting. The results from 2 in silico predictors, Splice AI (donor loss and acceptor gain) and VarSEAK (Class 5 splicing effect), provide evidence that correlates with a splicing impact to SERPINC1 function meeting criteria for PP3. This variant has been reported in 4 individuals with reported antithrombin activity level of < 0.8 IU/mL meeting PP4 and PS4_Moderate criteria (PMID 30975910, 28300866; Internal Thrombosis VCEP data). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP3, PP4, PM2_Supporting, PS4_ Moderate.

PP4

A single proband with unprovoked splanchnic DVT at age 34 with AT activity level of 56% with no family history of DVT but father reported as antithrombin deficient (no levels given) (internal thrombosis VCEP data).

PP3

The results from 2 in silico predictors, Splice AI (0.37 delta donor loss at -1bp and 0.76 delta donor gain at -42 bp) and VarSEAK (Class 5 splicing effect), provide evidence that correlates with a splicing impact to SERPINC1 function meeting criteria for PP3. This prediction at the exon/intron junction with a nucleotide overhang causes the insertion of 41 nucleotides GGT C| - CAA ACA GAT CCT TCC TCA AAG GAG GGA AGA GGT GGG CGT TC - |CA TAA CAA CGT CTT CCG, which causes

PS4_Moderate

3 points | A single proband with reported deep vein thrombosis and pulmonary embolism with repeat AT activity level of 58-59%. Two probands with a mean AT activity level of 55%.

PM2_Supporting

The variant is absent from gnomAD v2.1.1 and v3.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting.

Approved on: 2024-01-25

Published on: 2024-01-25

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