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_001386306.1:c.641A>C

CA343774510

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: eb962123-4c9a-4e58-88a9-05551c247ec8

HGVS expressions

NM_001386306.1:c.641A>C

NC_000001.11:g.173909848T>G

CM000663.2:g.173909848T>G

NC_000001.10:g.173878986T>G

CM000663.1:g.173878986T>G

NC_000001.9:g.172145609T>G

NG_012462.1:g.12531A>C

ENST00000367698.4:c.857A>C

ENST00000367698.3:c.857A>C

ENST00000487183.1:n.508A>C

ENST00000617423.4:c.559+2016A>C

NM_000488.3:c.857A>C

NM_001365052.1:c.713A>C

NM_000488.4:c.857A>C

NM_001365052.2:c.713A>C

NM_001386302.1:c.980A>C

NM_001386303.1:c.938A>C

NM_001386304.1:c.836A>C

NM_001386305.1:c.800A>C

Pathogenic

PS4 PP1_Strong PP4 PP3 PM2_Supporting

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.857A>C variant predicts a missense change at position 286, from Glutamine to Proline. The variant has been reported in at least 5 probands with AT deficiency along with multiple segregations in families in the literature (PMID: 28317092, 32862410). This missense variant is completely absent in gnomAD (v2.1.1 and v3.1.1). It has a REVEL score of 0.898 meeting the PP3 code. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP1_Strong, PS4, PP3, PP4, PM2_Supporting.

PS4

4 points (Family S is being used for PP4) - Mulder et al., 2017 (PMID: 28317092) reports two independent probands in Dutch families with type 1 deficiency. Proband #1 is a female (Family B) with VTE at 24 years of age with p.Gln286Pro and Type 1 deficiency (56% AT activity and 67% AT antigen levels). 8 family members in Family B tested and proven with AT deficiency and carriers of variant (no family members with normal AT activity and variant reported, pedigree not reported). Proband #2 is a female (Family E) with a VTE at 27yrs and activity level of 49%. At least two additional male patients are described in Bhoelan et al., 2021 (PMID: 32862410) as part of an experience paper of the use direct oral anticoagulant therapy in AT deficiency with deficient levels and positive family history.

PP1_Strong

Variant segregates in three families. Pedigrees are not provided, but the most conservative segregation number would be 14 (Family B = 8 + Family E = 3 + Family S = 3).

PP4

Female (Family S) with VTE at 62 years of age with p.Gln286Pro and Type 1 deficiency (49% AT activity and 49% AT antigen levels). 3 family members in Family S tested with AT deficiency and carriers of variant (3 family members with normal AT activity and variant reported).

PP3

REVEL score of 0.898 meets set threshold (>0.6). No splicing disruption prediction per SpliceAI and varSEAK. This variant introduces a Proline residue in the middle of a beta sheet secondary structure.

PM2_Supporting

The c.857A>C (p.Gln286Pro) (NM_000488.4) 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.

Approved on: 2024-01-25

Published on: 2024-01-25

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