Variant: NM_000488.4(SERPINC1):c.1301T>G (p.Phe434Cys)

CA343772451

627224 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

UUID: d46c80fa-aeac-4d2d-a3eb-c74213ad1557

Approved on: 2024-02-19

Published on: 2024-02-19

HGVS expressions

NM_000488.4:c.1301T>G
NM_000488.4(SERPINC1):c.1301T>G (p.Phe434Cys)
NC_000001.11:g.173903983A>C
CM000663.2:g.173903983A>C
NC_000001.10:g.173873121A>C
CM000663.1:g.173873121A>C
NC_000001.9:g.172139744A>C
NG_012462.1:g.18396T>G
ENST00000367698.4:c.1301T>G
ENST00000367698.3:c.1301T>G
ENST00000617423.4:c.686T>G
NM_000488.3:c.1301T>G
NM_001365052.1:c.1157T>G
NM_001365052.2:c.1157T>G
NM_001386302.1:c.1424T>G
NM_001386303.1:c.1382T>G
NM_001386304.1:c.1280T>G
NM_001386305.1:c.1244T>G
NM_001386306.1:c.1085T>G

Uncertain Significance

• Met criteria codes: PM5_Supporting PS4_Supporting PM2_Supporting PP3

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.1301T>G (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of phenylalanine by cystenine at amino acid 434 (p.Phe434Cys). This variant has been reported in 1 proband meeting an antithrombin activity level of < 0.8 IU/mL with repeat testing overtime (PS4_Supporting; PMID:1469094). This variant is absent from gnomAD v3.1.2 and v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.921, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1302C>A (p.Phe434Leu) (ClinVarID:2202884) in the same codon has been classified as likely pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant antithrombin III deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP3, PM2, PM5, PS4_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

• PM5_Supporting: Another missense variant c.1302C>A (p.Phe434Leu) (ClinVarID:2202884) in the same codon has been classified as likely pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5_Supporting).
• PS4_Supporting: This variant has been reported in 1 proband meeting an antithrombin activity level of < 0.8 IU/mL with repeat testing overtime (PS4_Supporting; PMID:1469094).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1,v3.1.2 and v4.0.0 (PM2_Supporting).
• PP3: The computational predictor REVEL gives a score of 0.921, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3).