NM_001386306.1:c.614_615del

CA1139771046

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

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

Approved on: 2023-09-21

Published on: 2023-09-29

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

• Met criteria codes: PP4 PP1_Strong PS4_Moderate PM2_Supporting PVS1

Expert Panel

Thrombosis VCEP

Criteria Specification Information

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.

Met criteria codes

• 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.
• 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.
• 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.