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.236G>A (p.Arg79His)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA210758

18014 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 43e159f4-6a9d-4030-8321-d7a5462a898f

Approved on: 2023-09-21

Published on: 2023-09-29

HGVS expressions

NM_000488.3:c.236G>A

NM_000488.3(SERPINC1):c.236G>A (p.Arg79His)

NC_000001.11:g.173914725C>T

CM000663.2:g.173914725C>T

NC_000001.10:g.173883863C>T

CM000663.1:g.173883863C>T

NC_000001.9:g.172150486C>T

NG_012462.1:g.7654G>A

ENST00000367698.4:c.236G>A

ENST00000367698.3:c.236G>A

ENST00000494024.1:n.462G>A

ENST00000617423.4:c.236G>A

NM_001365052.1:c.92G>A

NM_000488.4:c.236G>A

NM_001365052.2:c.92G>A

NM_001386302.1:c.236G>A

NM_001386303.1:c.317G>A

NM_001386304.1:c.236G>A

NM_001386305.1:c.236G>A

NM_001386306.1:c.236G>A

NM_000488.4(SERPINC1):c.236G>A (p.Arg79His)

Pathogenic

PS4 PM1 PP4 PP3 PP1_Strong

PM5 PM2 BS2 BS1

Evidence Links 1

Expert Panel

Thrombosis VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Thrombosis VCEP

The c.236G>A (p.Arg79His) variant is reported at an FAF of 0.0002303 and MAF of 0.0003380 (23/68044 alleles) in the non-Finnish European population in gnomAD v3.1.1 meeting BS1 criteria of MAF >0.0002. However, this variant is an established founder variant known as AT Padua I making it ineligible for the BS1 rule application. It has a REVEL score of 0.702, and meets PP3. At least 23 individuals with AT deficiency meeting the SERPINC1 phenotype criteria (other cases are reported but do not meet criteria) are reported in the literature meeting PS4_Very Strong and PP4. Additionally, 9 meioses have been reported across 16 families meeting PP1_Strong. In summary, this variant reaches a classification of pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Strong, PM1, PP3, PP4.

PS4

Many more than 8 individuals with AT deficiency meeting the SERPINC1 phenotype criteria are reported in the literature.

PM1

Variant disrupts a heparin binding site.

Disrupts heparin binding site. PubMed:2615648

PP4

Original report of variant ("Rouen") in proband with type II AT deficiency affecting heparin binding. Female and daughter were found to have reduced AT activity on Anti-IIa assay (55%). Couldn't confirm that daughter was genotyped.

PP3

The variant has a REVEL score of 0.702, and meets PP3 (threshold >0.6)

PP1_Strong

At least 9 meioses counted across 16 families.

PM5

Arg79Cys is another variant at the same residue that is provisionally classified as likely pathogenic by the Thrombosis VCEP. However, the Grantham difference for an Arg to Cys change is 180 while that for an Arg to His change is 29.

PM2

Variant FAF in gnomAD v3.1.1 meets BS1

BS2

Variant affects heparin binding and therefore can result in normal AT activity on certain assays.

BS1

The c.236G>A (p.Arg79His) variant is reported at an FAF of 0.0002303 and MAF of 0.0003380 (23/68044 alleles) in the non-Finnish European population in gnomAD v3.1.1 meeting BS1 criteria of MAF >0.0002. However, this variant has been deemed a founder variant and is excluded from BS1. Note, the variant is reported at an FAF of 0.00009544 and MAF of 0.0001781 (23/129164 alleles) in the non-Finnish European population in gnomAD v2.1.1 (which does not meet BS1)

Curation History

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