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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000488.4(SERPINC1):c.1274G>A (p.Arg425His)

CA210766

18019 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 90b0cc6b-fac4-4e73-a309-1759d8a91ed3

HGVS expressions

NM_000488.4:c.1274G>A

NM_000488.4(SERPINC1):c.1274G>A (p.Arg425His)

NC_000001.11:g.173904010C>T

CM000663.2:g.173904010C>T

NC_000001.10:g.173873148C>T

CM000663.1:g.173873148C>T

NC_000001.9:g.172139771C>T

NG_012462.1:g.18369G>A

ENST00000367698.4:c.1274G>A

ENST00000367698.3:c.1274G>A

ENST00000617423.4:c.659G>A

NM_000488.3:c.1274G>A

NM_001365052.1:c.1130G>A

NM_001365052.2:c.1130G>A

NM_001386302.1:c.1397G>A

NM_001386303.1:c.1355G>A

NM_001386304.1:c.1253G>A

NM_001386305.1:c.1217G>A

NM_001386306.1:c.1058G>A

Pathogenic

PM2_Supporting PP1_Moderate PS4 PP4 PP3

PVS1 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.1274G>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 425 (p.Arg425His; legacy nomenclature p.R393H aka Antithrombin Glasgow). The computational predictor REVEL gives a score of 0.806, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. This variant is at extremely low frequency (Total: 0.000003979, European (non-Finnish): 0.000008798) in gnomAD v2.1.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting (MAF <2.0 X 10-5). This variant has been reported in at least 16 probands in the literature with AT deficiency meeting PP4 and PS4_VeryStrong (PMID: 26134363; 27766527; 28607330; 28300866; 3179448). Additionally, this variant has been report in at least 4 meioses across 14 families meeting PP1_Moderate. In summary, based on the evidence available at this time, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Moderate, PP3, PP4, PM2_Supporting.

PM2_Supporting

This variant is at extremely low frequency (Total: 0.000003979, European (non-Finnish): 0.000008798) in gnomAD v2.1.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting (MAF < 2.0 X 10-5).

PP1_Moderate

Report of 18 individuals from 14 families with AT deficiency is at least 4 meioses.

PS4

This variant has been reported in at least 8 probands in the literature with AT deficiency meeting PS4_VeryStrong (PMID: 26134363; 27766527; 28607330; 28300866; 3179448)

PP4

Proband with AT activity of 70 and repeat testing.

PP3

The computational predictor REVEL gives a score of 0.806, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3.

PVS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

c.1273C>T, p.R425C is reported but Grantham score is higher R to C is 180 and R to H is 29. c.1274G>C, p.R425P is reported but Grantham score is higher R to C is 103 and R to H is 29. These variants have not yet been curated by the Thrombosis VCEP.

Approved on: 2023-09-21

Published on: 2023-09-29

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