Variant: NM_000488.4(SERPINC1):c.1171C>T (p.Arg391Ter)

Version: 1.0
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CA343772824

2734038 (ClinVar)

Gene: SERPINC1 (HGNC:462)

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

UUID: dcf417cb-44a7-42fd-ac34-f899ff29d765

Approved on: 2024-12-20

Published on: 2024-12-20

HGVS expressions

NM_000488.4:c.1171C>T
NM_000488.4(SERPINC1):c.1171C>T (p.Arg391Ter)
NC_000001.11:g.173907497G>A
CM000663.2:g.173907497G>A
NC_000001.10:g.173876635G>A
CM000663.1:g.173876635G>A
NC_000001.9:g.172143258G>A
NG_012462.1:g.14882C>T
ENST00000367698.4:c.1171C>T
ENST00000367698.3:c.1171C>T
ENST00000617423.4:c.560-4C>T
NM_000488.3:c.1171C>T
NM_001365052.1:c.1027C>T
NM_001365052.2:c.1027C>T
NM_001386302.1:c.1294C>T
NM_001386303.1:c.1252C>T
NM_001386304.1:c.1150C>T
NM_001386305.1:c.1114C>T
NM_001386306.1:c.955C>T

Pathogenic

• Met criteria codes: PS4_Moderate PP4 PP1_Strong PM2_Supporting PVS1_Strong

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.1171C>T (p.Arg391Ter) variant in SERPINC1 is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent studies, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:29153735). This variant has been reported in at least four more probands meeting an antithrombin activity level of < 0.8 IU/mL; due to the absence of specified repeat testing, crossed electrophoresis showing abnormal results and family members with reported antithrombin activity levels below the threshold three of these probands were scored at only half a point. (2.5 points) (PS4_Moderate; PMIDs:34207366, 8217824, 31030036, 23932013). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in 15 affected family members from two families (PP1_Strong; PMIDs:34207366, 23932013). The highest population minor allele frequency in gnomAD v4.1 is 0.000001 (2/1179816 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 pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PVS1_Strong, PP4, PS4_Moderate, PP1_Strong, PM2_Supporting. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval)

Met criteria codes

• PS4_Moderate: This variant has been reported in at least four more probands meeting an antithrombin activity level of < 0.8 IU/mL; due to the absence of specified repeat testing, crossed electrophoresis showing abnormal results and family members with reported antithrombin activity levels below the threshold three of these probands were scored at only half a point. (2.5 points) (PS4_Moderate; PMIDs:34207366, 8217824, 31030036, 23932013).
• PP4: At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent studies, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:29153735).
• PP1_Strong: The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in 15 affected family members from two families (PP1_Strong; PMIDs:34207366, 23932013).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1 is 0.000001 (2/1179816 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).
• PVS1_Strong: The c.1171C>T (p.Arg391Ter) variant in SERPINC1 is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong).