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]

Variant: NM_000488.3(SERPINC1):c.218C>T (p.Pro73Leu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA210756

18011 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b7a99380-d40e-4611-81d1-d60401803a33

Approved on: 2023-09-21

Published on: 2023-09-29

HGVS expressions

NM_000488.3:c.218C>T

NM_000488.3(SERPINC1):c.218C>T (p.Pro73Leu)

NC_000001.11:g.173914743G>A

CM000663.2:g.173914743G>A

NC_000001.10:g.173883881G>A

CM000663.1:g.173883881G>A

NC_000001.9:g.172150504G>A

NG_012462.1:g.7636C>T

ENST00000367698.4:c.218C>T

ENST00000367698.3:c.218C>T

ENST00000494024.1:n.444C>T

ENST00000617423.4:c.218C>T

NM_001365052.1:c.74C>T

NM_000488.4:c.218C>T

NM_001365052.2:c.74C>T

NM_001386302.1:c.218C>T

NM_001386303.1:c.299C>T

NM_001386304.1:c.218C>T

NM_001386305.1:c.218C>T

NM_001386306.1:c.218C>T

NM_000488.4(SERPINC1):c.218C>T (p.Pro73Leu)

Pathogenic

PP1_Strong PS4 PP4 PP3 PM1

PS3 PM2

Evidence Links 0

Expert Panel

Thrombosis VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Thrombosis VCEP

The c.218C>T (p.Pro73Leu) variant is reported at a POPMAX FAF of 0.0007473 in exomes in gnomAD v2.1.1 and at an FAF of 0.0006639 in genomes in gnomAD v3.1.1 in the non-Finnish European population. The frequency does not meet the threshold for PM2_Supporting. At least 30 probands with AT deficiency and several others from internal laboratory data are reported with AT tests on 2 independent samples, meeting criteria for PS4_VeryStrong and PP4. There at least 17 meioses out of 35 families meeting PP1_Strong (PMID:28300866). This missense variant has a REVEL score of 0.658 (threshold >0.6), meeting criteria for PP3, and is within a heparin binding site, meeting PM1. 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: PS4_VeryStrong, PP1_Strong, PM1, PP3, PP4.

PP1_Strong

PP1 applied based on at least 17 segregations seen across 35 families.

PS4

At least 30 probands with AT deficiency and several others from internal laboratory data are reported with AT tests on 2 independent samples, meeting criteria for PS4_VeryStrong (>8 probands).

PP4

3 probands with AT activity level of 57% (47-68) with VTE reported.

PP3

This missense variant has a REVEL score of 0.658 (threshold >0.6), meeting criteria for PP3

PM1

Heparin binding site residue.

PS3

The Pro73Leu variant was expressed in HEK-EBNA cells to evaluate heparin-binding by crossed immunoelectrophoresis, which revealed that the mutant β-glycoform retained a component with high heparin affinity. However, antigen or activity levels are not specified. PS3 criteria not met.

PM2

The c.218C>T (p.Pro73Leu) variant is reported at a POPMAX FAF of 0.0007473 in exomes in gnomAD v2.1.1 and at an FAF of 0.0006639 in genomes in gnomAD v3.1.1 in the non-Finnish European population. The frequency does not meet the threshold of <= 2.0 X 10-5. Of note, the variant is observed at a frequency of 0.004458 (0.4%) in the Finnish European population, where a founder effect is suggested. (PMID: 23910795)

Curation History

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