Variant: NM_000488.4(SERPINC1):c.1246G>C (p.Ala416Pro)

CA210750

18007 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

UUID: 4bc692de-2d73-4e56-82ca-fbe9d67c85e9

Approved on: 2024-12-20

Published on: 2024-12-20

HGVS expressions

NM_000488.4:c.1246G>C
NM_000488.4(SERPINC1):c.1246G>C (p.Ala416Pro)
NC_000001.11:g.173904038C>G
CM000663.2:g.173904038C>G
NC_000001.10:g.173873176C>G
CM000663.1:g.173873176C>G
NC_000001.9:g.172139799C>G
NG_012462.1:g.18341G>C
ENST00000367698.4:c.1246G>C
ENST00000367698.3:c.1246G>C
ENST00000617423.4:c.631G>C
NM_000488.3:c.1246G>C
NM_001365052.1:c.1102G>C
NM_001365052.2:c.1102G>C
NM_001386302.1:c.1369G>C
NM_001386303.1:c.1327G>C
NM_001386304.1:c.1225G>C
NM_001386305.1:c.1189G>C
NM_001386306.1:c.1030G>C

Pathogenic

• Met criteria codes: PM2_Supporting PS4_Moderate PP4 PP3 PP1_Strong PM1 PM5

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.1246G>C variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by proline at amino acid 416 (p.Ala416Pro). At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL and abnormal crossed electrophoresis, which is highly specific for autosomal dominant hereditary antithrombin deficiency (PP4, PMID:4082101). This variant has been reported in two more probands meeting an antithrombin activity level of < 0.8 IU/mL and a family history of disease with reported decreased antithrombin activity levels (PS4_Moderate; PMID:24583439, 2093312). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in at least 9 affected meioses from 4 families (PP1_Strong; PMID:33725558, 4082101, 24583439, 2093312). This variant resides within an reactive site residues (Ala416) of SERPINC1 that is defined as a critical functional domain by the ClinGen Thrombosis VCEP (PM1). Another missense variant c.1246G>T (p.Ala416Ser) (ClinVarID:18023) in the same codon has been classified as pathogenic for autosomal dominant hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). The computational predictor REVEL gives a score of 0.837, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1_strong, PM1, PM5, PS4_moderate, PP3, PP4, PM2_supporting.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• PS4_Moderate: This variant has been reported in two more probands meeting an antithrombin activity level of < 0.8 IU/mL and a family history of disease with reported decreased antithrombin activity levels (PS4_Moderate; PMID:24583439, 2093312).
• PP4: At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL and abnormal crossed electrophoresis, which is highly specific for autosomal dominant hereditary antithrombin deficiency (PP4, PMID:4082101).
• PP3: The computational predictor REVEL gives a score of 0.837, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3).
• PP1_Strong: The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in at least 9 affected meioses from 4 families (PP1_Strong; PMID:33725558, 4082101, 24583439, 2093312).
• PM1: This variant resides within an reactive site residues (Ala416) of SERPINC1 that is defined as a critical functional domain by the ClinGen Thrombosis VCEP (PM1).
• PM5: Another missense variant c.1246G>T (p.Ala416Ser) (ClinVarID:18023) in the same codon has been classified as pathogenic for autosomal dominant hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5).