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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CA1139771046

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b3cb2eba-1943-46dc-b940-3f7a78064430

HGVS expressions

NM_001386306.1:c.614_615del

NC_000001.11:g.173909877_173909878del

CM000663.2:g.173909877_173909878del

NC_000001.10:g.173879015_173879016del

CM000663.1:g.173879015_173879016del

NC_000001.9:g.172145638_172145639del

NG_012462.1:g.12504_12505del

ENST00000367698.4:c.830_831del

ENST00000367698.3:c.830_831del

ENST00000487183.1:n.481_482del

ENST00000617423.4:c.559+1989_559+1990del

NM_000488.3:c.830_831del

NM_001365052.1:c.686_687del

NM_000488.4:c.830_831del

NM_001365052.2:c.686_687del

NM_001386302.1:c.953_954del

NM_001386303.1:c.911_912del

NM_001386304.1:c.809_810del

NM_001386305.1:c.773_774del

Pathogenic

PS4_Moderate PM2_Supporting PVS1 PP1_Strong PP4

Evidence Links 0

Expert Panel

Thrombosis VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Thrombosis VCEP

The variant SERPINC1 p.Glu277ValfsTer20 is predicted to lead to a loss of function by nonsense mediated mRNA decay (NMD) with the being exon present in biologically relevant transcripts. The variant has been reported in 5 individuals in the literature (PMID: 33220012, 30721820, 1868237, 33725558) meeting the SERPINC1 phenotype criteria; however only 1 of them was reported with repeat AT testing meeting PP4 and PS4_Moderate criteria. To date, the variant has not been reported in the general population (gnomAD v2.1.1 and v3.1) found in neither the genomes nor exomes meeting PM2_Supporting. The variant has been reported in 18 segregations across 3 families in the literature meeting PP1_Strong (PMIDs: 33220012, 1868237, 33725558). 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: PVS1, PP1_strong, PS4_Moderate, PP4, PM2_supporting.

PS4_Moderate

Total 2.5 point | 4 probands across the literature are reported with the variant and AT deficiency with and without family history

PM2_Supporting

The variant is absent from gnomAD v2.1.1 and v3.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting

PVS1

Variant is predicted to undergo NMD and exon is present in biologically relevant transcripts, meeting criteria for PVS1.

PP1_Strong

18 segregations across 3 families are counted in the literature (PMIDs: 33220012, 1868237, 33725558) meeting criteria (>7 meioses within >2 families) for PP1_Strong.

PP4

1-1, female proband in family 1, is described with the Glu277ValfsTer20 variant and AT deficiency. Functional and immunological testing were noted to be repeated. First DVT is noted at 26y.

Approved on: 2023-09-21

Published on: 2023-09-29

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