Variant: NM_000488.4(SERPINC1):c.1240G>A (p.Ala414Thr)

CA210768

18020 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

UUID: 4ce45580-d377-4c7c-a7bf-b38f0c4096a3

Approved on: 2024-12-20

Published on: 2024-12-20

HGVS expressions

NM_000488.4:c.1240G>A
NM_000488.4(SERPINC1):c.1240G>A (p.Ala414Thr)
NC_000001.11:g.173904044C>T
CM000663.2:g.173904044C>T
NC_000001.10:g.173873182C>T
CM000663.1:g.173873182C>T
NC_000001.9:g.172139805C>T
NG_012462.1:g.18335G>A
ENST00000367698.4:c.1240G>A
ENST00000367698.3:c.1240G>A
ENST00000617423.4:c.625G>A
NM_000488.3:c.1240G>A
NM_001365052.1:c.1096G>A
NM_001365052.2:c.1096G>A
NM_001386302.1:c.1363G>A
NM_001386303.1:c.1321G>A
NM_001386304.1:c.1219G>A
NM_001386305.1:c.1183G>A
NM_001386306.1:c.1024G>A

Likely Pathogenic

• Met criteria codes: PP1 PP4 PP3 PM1 PM2_Supporting PS4_Moderate

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.1240G>A variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 414 (p.Ala414Thr). At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:36764659). This variant has been reported in 4 more probands meeting an antithrombin activity level of < 0.8 IU/mL on repeated independent tests or a family history of disease with reported antithrombin levels (PS4_Moderate, 3.5pts; PMID:25466846, 24684277, 3179438, 28300866). One proband did not meet the full requirements and thus half a point is awarded. The variant has been reported to segregate with hereditary antithrombin deficiency in at least 2 additional affected family members from one family (PP1; PMID:3179438). This variant resides within a residue, Ala414, of SERPINC1 that is defined as a reactive site residue by the ClinGen Thrombosis VCEP (PMID:2615648, PM1). The computational predictor REVEL gives a score of 0.85, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000003390 (4/1180010 alleles) in European (non-Finnish) population, which is lower than the ClinGen Thrombosis VCEP threshold (<0.00002) for PM2_Supporting, meeting this criterion (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: PM1, PS4_moderate, PP1, PP3, PP4, PM2_supporting.

Met criteria codes

• PP1: The variant has been reported to segregate with hereditary antithrombin deficiency in at least 2 additional affected family members from one family (PP1; PMID:3179438).
• PP4: At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:36764659).
• PP3: The computational predictor REVEL gives a score of 0.85, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3).
• PM1: This variant resides within a residue, Ala414, of SERPINC1 that is defined as a reactive site residue by the ClinGen Thrombosis VCEP (PMID:2615648, PM1).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0 is 0.000003390 (4/1180010 alleles) in European (non-Finnish) population, which is lower than the ClinGen Thrombosis VCEP threshold (<0.00002) for PM2_Supporting, meeting this criterion (PM2_Supporting).
• PS4_Moderate: This variant has been reported in 4 probands meeting an antithrombin activity level of < 0.8 IU/mL on repeated independent tests or a family history of disease with reported antithrombin levels (PS4_Moderate, 3.5pts; PMID:25466846, 24684277, 3179438, 28300866).