Variant: NM_000488.4(SERPINC1):c.1274G>C (p.Arg425Pro)

CA210752

18009 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

UUID: 448c7154-1578-4ece-aaf2-68c695367358

Approved on: 2024-07-03

Published on: 2024-09-30

HGVS expressions

NM_000488.4:c.1274G>C
NM_000488.4(SERPINC1):c.1274G>C (p.Arg425Pro)
NC_000001.11:g.173904010C>G
CM000663.2:g.173904010C>G
NC_000001.10:g.173873148C>G
CM000663.1:g.173873148C>G
NC_000001.9:g.172139771C>G
NG_012462.1:g.18369G>C
ENST00000367698.4:c.1274G>C
ENST00000367698.3:c.1274G>C
ENST00000617423.4:c.659G>C
NM_000488.3:c.1274G>C
NM_001365052.1:c.1130G>C
NM_001365052.2:c.1130G>C
NM_001386302.1:c.1397G>C
NM_001386303.1:c.1355G>C
NM_001386304.1:c.1253G>C
NM_001386305.1:c.1217G>C
NM_001386306.1:c.1058G>C

Likely Pathogenic

• Met criteria codes: PS4_Supporting PP3 PP1_Moderate PM5 PM2_Supporting

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

Evidence submitted by expert panel

Thrombosis VCEP

The c.1274G>C variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by proline at amino acid 425 (p.Arg425Pro). This variant has been reported in one proband meeting an antithrombin activity level of < 0.8 IU/mL with a family history of antithrombin activity levels of < 0.8 IU/mL (PS4_Supporting; PMID:3828226, 2722864). The variant has been reported to segregate with hereditary antithrombin deficiency in seven affected meioses from the proband's family (PP1_Moderate; PMID: 3828226). The computational predictor REVEL gives a score of 0.878, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1274G>A (p.Arg425His) (ClinVarID:18019) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PM2_Supporting, PS4_Supporting, PP3, PM5, PP1_Moderate.

Met criteria codes

• PS4_Supporting: This variant has been reported in one proband meeting an antithrombin activity level of < 0.8 IU/mL with a family history of antithrombin activity levels of < 0.8 IU/mL (PS4_Supporting; PMID:3828226, 2722864).
• PP3: The computational predictor REVEL gives a score of 0.878, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3).
• PP1_Moderate: The variant has been reported to segregate with hereditary antithrombin deficiency in seven additional affected meioses from one family (PP1_Moderate; PMID: 3828226).
• PM5: Another missense variant c.1274G>A (p.Arg425His) (ClinVarID:18019) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting).