Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000488.4(SERPINC1):c.1376C>A (p.Ala459Asp)

CA343772066

626996 (ClinVar)

Gene: SERPINC1
Condition: antithrombin III deficiency
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: bc8c74bf-27b3-46b9-855b-d2e5eaab32f8
Approved on: 2024-12-20
Published on: 2024-12-20

HGVS expressions

NM_000488.4:c.1376C>A
NM_000488.4(SERPINC1):c.1376C>A (p.Ala459Asp)
NC_000001.11:g.173903908G>T
CM000663.2:g.173903908G>T
NC_000001.10:g.173873046G>T
CM000663.1:g.173873046G>T
NC_000001.9:g.172139669G>T
NG_012462.1:g.18471C>A
ENST00000367698.4:c.1376C>A
ENST00000367698.3:c.1376C>A
ENST00000617423.4:c.761C>A
NM_000488.3:c.1376C>A
NM_001365052.1:c.1232C>A
NM_001365052.2:c.1232C>A
NM_001386302.1:c.1499C>A
NM_001386303.1:c.1457C>A
NM_001386304.1:c.1355C>A
NM_001386305.1:c.1319C>A
NM_001386306.1:c.1160C>A
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Uncertain Significance

Met criteria codes 4
PS3_Supporting PM2_Supporting PS4_Supporting PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Thrombosis VCEP
The c.1376C>A variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by aspartic acid at amino acid 459 (p.Ala459Asp). This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL. One proband had a family history of disease with reported antithrombin activity level and one proband had a family history of disease but no antithrombin activity level was reported (PS4_Supporting; PMIDs: 8401542, 23809926). This variant is absent from gnomAD v2.1.1, v3.1.2 and v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.756, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). AT activity levels are shown to be reduced (27%) of WT when Ala459Asp was expressed in COS (PMID: 23809926), meeting criteria for PS3_Supporting. In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP3, PM2_Supporting, PS4_Supporting, PS3_Supporting.
Met criteria codes
PS3_Supporting
AT activity levels are shown to be reduced (27%) of WT when Ala459Asp was expressed in COS (PMID: 23809926), meeting criteria for PS3_Supporting.
PM2_Supporting
This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting).
PS4_Supporting
This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL. One proband had a family history of disease with reported antithrombin activity level and one proband had a family history of disease but no antithrombin activity level was reported (PS4_Supporting; PMIDs: 8401542, 23809926).
PP3
The computational predictor REVEL gives a score of 0.756, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3).
Curation History
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