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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000488.4(SERPINC1):c.1277C>T (p.Ser426Leu)

CA210754

18010 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ffe46634-e8bb-401d-8f67-a4d2202b094b

Approved on: 2023-09-21

Published on: 2024-08-21

HGVS expressions

NM_000488.4:c.1277C>T

NM_000488.4(SERPINC1):c.1277C>T (p.Ser426Leu)

NC_000001.11:g.173904007G>A

CM000663.2:g.173904007G>A

NC_000001.10:g.173873145G>A

CM000663.1:g.173873145G>A

NC_000001.9:g.172139768G>A

NG_012462.1:g.18372C>T

ENST00000367698.4:c.1277C>T

ENST00000367698.3:c.1277C>T

ENST00000617423.4:c.662C>T

NM_000488.3:c.1277C>T

NM_001365052.1:c.1133C>T

NM_001365052.2:c.1133C>T

NM_001386302.1:c.1400C>T

NM_001386303.1:c.1358C>T

NM_001386304.1:c.1256C>T

NM_001386305.1:c.1220C>T

NM_001386306.1:c.1061C>T

Pathogenic

PS4 PM2_Supporting PP4 PP3 PS3_Supporting PP1_Strong

Evidence Links 0

Expert Panel

Thrombosis VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Thrombosis VCEP

The NM_000488.4(SERPINC1):c.1277C>T variant predicts a missense change from Serine to Leucine at position 426. Several probands and related individuals are reported in the literature with antithrombin deficiency and the Ser426Leu variant, meeting criteria for PS4 and PP4 (multiple publications). The variant was seen across a total of 8 meioses amongst 3 families meeting PP1_Strong (PMID: 30721820, 3512602, 3563966). The variant was shown to impair complex formation with thrombin when the variant was expressed in rabbit reticulocytes (PMID: 2207328). The variant is absent in gnomAD (v2.1.1 and v3.1.1) meeting PM2_Supporting. It has a REVEL score of 0.88, which meets the PP3 set threshold (>0.6). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel: PS4, PP1_Strong, PP3, PP4, PS3_Supporting, PM2_Supporting.

PS4

7 Points - This variant was first reported in 1986 simultaneously on the US (Denver) and Italy (Milano-2). In Italy the was described as part of four members of an Italian family (two with histories of venous thromboembolism) and a consistently borderline low (about 70% of normal) qualitative defect of antithrombin III with normal antigen concentrations (Tripodi et al., 1986; PMID: 3563966) and the specific DNA variant later defined (Olds et al., PMID: 2602168). 7 French individuals from 6 families with type 2 RS deficiency and measured mean antithrombin activity of 65% and normal antigen levels (Alhenc-Gelas et al., 2017; PMID: 28300866) are heterozygote carriers. Additionally, 5 Danish individuals from 2 families with type 2 RS deficiency and measured antithrombin activity of 64% (58-70% range) with 38-45 years in range and 3 with documented VT (at age 16, 18 and 36yo) and 1 with recurrent PE (Kjaergaard et al., 2019; PMID: 30721820) carry the variant in heterozygosity. Finally, a 8yo deceased Spanish heterozygote female (No. 64, Cohort 1) with PE (OCP risk factor) is reported with 60% of antithrombin activity and classified as Type 2 HBS (Morena-Barrio et al., 2019: PMID: 30975910). Another case with overlapping authors was reported with limited detail, but confirmed repeat sampling, so this case was counted instead out of an abundance of caution (Bravo-Pérez et al., 2022; PMID: 34800304). Two heterozygote carriers were not included. First, a single individual (unspecified gender or age) from a Japanese cohort of 173 individuals with DVT is a heterozygote carrier. Normal anti-thrombin measurement (113%) (Miyata et al., 2008; PMID: 18954896). Second, a 20-year-old African female (risk factors: BMI, first trimester pregnancy), heterozygote carrier of this variant with recurrent miscarriages and acute unprovoked idiopathic fatal pulmonary embolism (IFPE). No anti-thrombin measurement, thus not included in final count (Halvorsen et al., 2017; PMID: 28174134).

PM2_Supporting

The variant is absent in gnomAD (v2.1.1 and v3.1.1). There is good coverage profile across both genomes and exomes in this region.

PP4

In the US, a 16yo female proband with DVT, 2 months after OCP initiation and recurrence during pregnancy was evaluated in Denver, Colorado with 54% AT activity; multiple AT assays performed.

PP3

REVEL score of 0.88 meets set threshold (>0.6). No splicing disruption prediction per SpliceAI and varSEAK.

PS3_Supporting

The first report in Italy included assessment with the proband plasma of the AT affinity to immobilized human alpha-thrombin ion sepharose beads revealing defective binding of the antithrombin III to thrombin-sepharose, locating the variant in the active site responsible for binding and neutralizing thrombin (Olds et al., 1989; PMID: 2602168). This missense variant was also constructed with site-directed mutagenesis into a cell system, expressed (translated using rabbit reticulocytes) and purified to assess impaired complex formation with thrombin through chromatography (Austin et al., 1990; PMID: 2207328) and document the affected residue is essential for proper antithrombin activity.

PP1_Strong

Total of 8 meioses amongst 3 families.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.