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_000488.4(SERPINC1):c.449A>C (p.Gln150Pro)

CA1251409

654211 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6fdd3bac-395e-4fdd-9e42-2c552b360524

Approved on: 2024-05-09

Published on: 2024-05-09

HGVS expressions

NM_000488.4:c.449A>C

NM_000488.4(SERPINC1):c.449A>C (p.Gln150Pro)

NC_000001.11:g.173911974T>G

CM000663.2:g.173911974T>G

NC_000001.10:g.173881112T>G

CM000663.1:g.173881112T>G

NC_000001.9:g.172147735T>G

NG_012462.1:g.10405A>C

ENST00000367698.4:c.449A>C

ENST00000367698.3:c.449A>C

ENST00000487183.1:n.154A>C

ENST00000617423.4:c.449A>C

NM_000488.3:c.449A>C

NM_001365052.1:c.305A>C

NM_001365052.2:c.305A>C

NM_001386302.1:c.449A>C

NM_001386303.1:c.530A>C

NM_001386304.1:c.449A>C

NM_001386305.1:c.449A>C

NM_001386306.1:c.409-1083A>C

Likely Pathogenic

PS4 PP3 PP4 PM2_Supporting

Evidence Links 0

Expert Panel

Thrombosis VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Thrombosis VCEP

The NM_000488.4:c.449A>C variant in SERPINC1 is a missense variant predicted to cause substitution of Glutamine by Proline at amino acid 150 (p.Gln150Pro). This variant is also known as antithrombin Vienna (Legacy nomenclature: Gln118Pro) in the literature. At least one patient with this variant displayed AT deficiency (type II- HBD) which is highly specific for SERPINC1 (PP4, PMID: 7734360). The computational predictor REVEL gives a score of 0.865, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 gene function. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008791 (1/113750 alleles) in the non-Finnish European population, which is lower than the ClinGen Thrombosis VCEP threshold (<0.00002 ) for PM2_Supporting, meeting this criterion. In summary, this variant meets the criteria to be classified as a pathogenic for antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP. (Specifications version 1.0.0; date of approval: 7/17/2023).

PS4

Potentially 10 individuals with this variant and AT deficiency would contribute 10 points towards PS4_VeryStrong. To be updated following expert review.

PP3

The computational predictor REVEL gives a score of 0.865, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 gene function.

PP4

At least one patient with this variant displayed AT deficiency (type II- HBD) which is highly specific for SERPINC1 (PP4, PMID: 7734360)

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008791 (1/113750 alleles) in the non-Finnish European population, which is lower than the ClinGen Thrombosis VCEP threshold (<0.00002 ) for PM2_Supporting, meeting this criterion.

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