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.1154-14G>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA16609956

410384 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8fd70877-018a-48f9-9f44-947c2aa4cf8a

Approved on: 2023-09-21

Published on: 2023-09-29

HGVS expressions

NM_000488.3:c.1154-14G>A

NM_000488.3(SERPINC1):c.1154-14G>A

NC_000001.11:g.173907528C>T

CM000663.2:g.173907528C>T

NC_000001.10:g.173876666C>T

CM000663.1:g.173876666C>T

NC_000001.9:g.172143289C>T

NG_012462.1:g.14851G>A

ENST00000367698.4:c.1154-14G>A

ENST00000367698.3:c.1154-14G>A

ENST00000617423.4:c.560-35G>A

NM_001365052.1:c.1010-14G>A

NM_000488.4:c.1154-14G>A

NM_001365052.2:c.1010-14G>A

NM_001386302.1:c.1277-14G>A

NM_001386303.1:c.1235-14G>A

NM_001386304.1:c.1133-14G>A

NM_001386305.1:c.1097-14G>A

NM_001386306.1:c.938-14G>A

NM_000488.4(SERPINC1):c.1154-14G>A

Pathogenic

PP1_Moderate PS4 PM2_Supporting PP4 PP3 PM4

Evidence Links 0

Expert Panel

Thrombosis VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Thrombosis VCEP

The NM_000488.3(SERPINC1):c.1154-14G>A variant is completely absent from gnomAD v2.1.1 and v3.1, meeting criteria for PM2_supporting. More than 20 probands across publications and internal laboratory data meet AT deficiency phenotype criteria and therefore, PS4_Very Strong is applied. 6 segregations across 4 families are counted in the literature (PMIDs: 7981186, 15164384, 7949130, 32686144), so PP1_Moderate is applied. SpliceAI predicts a cryptic acceptor splice site at -2bp with a score of 0.5. At least 2 publications (PMID: 7949130, PMID: 30046692) show experimental evidence of alternative splicing in patients due to the variant and therefore, PP3 is applied. The splicing aberration results in addition of 12bp of intron 4 into exon 5 of SERPINC1, increasing the protein length by 4 amino acids. This region is noted to be important for the folding and polymerization of the protein. Therefore, PM4 is applied. 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_Very Strong, PM4, PP1_Moderate, PP3, PM2_Supporting.

PP1_Moderate

6 segregations across 4 families are counted in the literature (PMIDs: 7981186, 15164384, 7949130, 32686144).

PS4

>20 points | Several probands across publications and from internal laboratory data meet AT deficiency phenotype criteria with or without repeat testing and family history; and therefore, PS4_Very Strong is applied.

PM2_Supporting

The variant is absent from gnomAD v2.1.1 and v3.1, meeting criteria for PM2_supporting

PP4

Proband from Park et al, 2018 meets phenotype criteria with repeat testing

PP3

SpliceAI predicts a cryptic acceptor splice site at -2bp with a score of 0.5. Evidence must be reviewed prior to assigning PP3. At least 2 publications (PMID: 7949130, PMID: 30046692) show experimental evidence of alternative splicing in patients due to the variant. Therefore, PP3 is applied.

PM4

The splicing aberration results in addition of 12bp of intron 4 into exon 5 of SERPINC1, increasing the protein length by 4 amino acids. This region is noted to be important for the folding and polymerization of the protein, and the variant results in defective polymerization.

Curation History

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