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]

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Variant: NM_000488.3(SERPINC1):c.1315C>A (p.Pro439Thr)

CA343772370

627228 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1030c18a-bb25-4557-a2d7-449ce81e8f9d

HGVS expressions

NM_000488.3:c.1315C>A

NM_000488.3(SERPINC1):c.1315C>A (p.Pro439Thr)

NC_000001.11:g.173903969G>T

CM000663.2:g.173903969G>T

NC_000001.10:g.173873107G>T

CM000663.1:g.173873107G>T

NC_000001.9:g.172139730G>T

NG_012462.1:g.18410C>A

ENST00000367698.4:c.1315C>A

ENST00000367698.3:c.1315C>A

ENST00000617423.4:c.700C>A

NM_001365052.1:c.1171C>A

NM_000488.4:c.1315C>A

NM_001365052.2:c.1171C>A

NM_001386302.1:c.1438C>A

NM_001386303.1:c.1396C>A

NM_001386304.1:c.1294C>A

NM_001386305.1:c.1258C>A

NM_001386306.1:c.1099C>A

NM_000488.4(SERPINC1):c.1315C>A (p.Pro439Thr)

Pathogenic

PM2_Supporting PS3_Supporting PP1_Moderate PS4 PP4 PP3

PM5

Evidence Links 0

Expert Panel

Thrombosis VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Thrombosis VCEP

The c.1315C>A (p.Pro439Thr) variant is reported at an MAF of (FAF not available), 1/68048 alleles in the non-Finnish European population in gnomAD v3.1.1 and meets criteria for PM2_Supporting (threshold <0.00002). It has a REVEL score of 0.88 and meets criteria for PP3. Several probands can be counted across the literature, who meet phenotype criteria for AT deficiency with a mix of repeat sampling, meeting PP4 and PS4. Four segregations are counted across two families meeting criteria for PP1_Moderate. Expression of mutant AT, 439Thr-AT, in HEK293 cells described in PMID: 18480576 revealed decrease in AT secretion, meeting criteria for PS3_Supporting. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4, PP1_Moderate, PP3, PP4, PM2_Supporting, PS3_Supporting.

PM2_Supporting

The c.1315C>A (p.Pro439Thr) variant is reported at an MAF (FAF not available) of 0.00001470 (1/68048 alleles) in the non-Finnish European population, and meets criteria for PM2_Supporting.

PS3_Supporting

Expression of mutant AT, 439Thr-AT, in HEK293 cells described in PMID: 18480576 revealed decrease in AT secretion - 74%, and slight decrease in progressive activity - 84%, and heparin cofactor activity of 83%. PS3_Supporting applied based on reduced AT antigen levels.

PP1_Moderate

Two families with a total of 4 meioses between them meeting the PP1_Moderate criteria.

PS4

Total 4 points | Several probands counted across the literature, who meet phenotype criteria for AT deficiency with a mix of repeat sampling reported.

PP4

25yo Malay woman is reported with AT deficiency and the Pro439Thr variant. She presented with severe venous thrombo sis of the saphenofemoral junction up to the external iliac vein. AT level at the time of pregnancy and on anti-coagulant therapy was 37.4%. Repeated testing at 4m and 1y post-delivery revealed 58.3% and 49.8%, respectively.

PP3

The variant has a REVEL score of 0.88 and meets the threshold for PP3

PM5

Three other variants at the same residue, Pro439Ala (GD: 27), Pro439Leu (GD: 98) and Pro439Ser (GD: 74) are reported in the literature and are provisionally curated by the Thrombosis VCEP as VUS. Grantham difference for Pro439Thr is 38, which is greater than that of Pro439Ala.

Approved on: 2023-09-21

Published on: 2023-09-29

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