Variant: NM_000488.4(SERPINC1):c.1306G>A (p.Ala436Thr)

CA210746

18003 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

UUID: ddd2c25e-96fb-4e8e-b604-fab2f19d4825

Approved on: 2024-08-16

Published on: 2024-08-21

HGVS expressions

NM_000488.4:c.1306G>A
NM_000488.4(SERPINC1):c.1306G>A (p.Ala436Thr)
NC_000001.11:g.173903978C>T
CM000663.2:g.173903978C>T
NC_000001.10:g.173873116C>T
CM000663.1:g.173873116C>T
NC_000001.9:g.172139739C>T
NG_012462.1:g.18401G>A
ENST00000367698.4:c.1306G>A
ENST00000367698.3:c.1306G>A
ENST00000617423.4:c.691G>A
NM_000488.3:c.1306G>A
NM_001365052.1:c.1162G>A
NM_001365052.2:c.1162G>A
NM_001386302.1:c.1429G>A
NM_001386303.1:c.1387G>A
NM_001386304.1:c.1285G>A
NM_001386305.1:c.1249G>A
NM_001386306.1:c.1090G>A

Likely Pathogenic

• Met criteria codes: PS4_Moderate PP3 PM2_Supporting PP1_Moderate

• Not Met criteria codes: PM1

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.1306G>A (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 436 (p.Ala436Thr). This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL with either a family history of antithrombin activity levels of < 0.8 IU/mL or an abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function. One more proband is reported with antithrombin activity levels of < 0.8 IU/mL but no repeat testing or family history is specified so 0.5 point is awarded (PS4_Moderate; PMID:3055413, 1469094). The variant has been reported to segregate with autosomal dominant antithrombin deficiency in 11 affected meioses from one family (PP1_Moderate; PMIDs:1469094, 3055413). The computational predictor REVEL gives a score of 0.778, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (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: PP1_Moderate, PM2_Supporting, PS4_Moderate, PP3.

Met criteria codes

• PS4_Moderate: This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL with either a family history of antithrombin activity levels of < 0.8 IU/mL or an abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function. One more proband is reported with antithrombin activity levels of < 0.8 IU/mL but no repeat testing or family history is specified so 0.5 point is awarded. (PS4_Moderate; PMID:3055413, 1469094).
• PP3: The computational predictor REVEL gives a score of 0.778, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 and gnomAD v4.0.0 (PM2_Supporting).
• PP1_Moderate: The variant has been reported to segregate with autosomal dominant antithrombin deficiency in 11 affected meioses from one family (PP1_Moderate; PMIDs:1469094, 3055413).

Not Met criteria codes

• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline