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_000488.4(SERPINC1):c.655A>G (p.Asn219Asp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA210798

18042 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9482d4bb-1f00-4a9d-b00d-13d6a0fdea2c

Approved on: 2023-09-21

Published on: 2023-09-29

HGVS expressions

NM_000488.4:c.655A>G

NM_000488.4(SERPINC1):c.655A>G (p.Asn219Asp)

NC_000001.11:g.173910861T>C

CM000663.2:g.173910861T>C

NC_000001.10:g.173879999T>C

CM000663.1:g.173879999T>C

NC_000001.9:g.172146622T>C

NG_012462.1:g.11518A>G

ENST00000367698.4:c.655A>G

ENST00000367698.3:c.655A>G

ENST00000487183.1:n.330-24A>G

ENST00000617423.4:c.559+1003A>G

NM_000488.3:c.655A>G

NM_001365052.1:c.511A>G

NM_001365052.2:c.511A>G

NM_001386302.1:c.655A>G

NM_001386303.1:c.736A>G

NM_001386304.1:c.655A>G

NM_001386305.1:c.655A>G

NM_001386306.1:c.439A>G

Pathogenic

PP1_Strong PS4 PM2_Supporting PP4 PP3

PM5

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(SERPINC1):c.655A>G (p.Asn219Asp) missense variant is reported at a Popmax FAF of 0.00000488 (non-Finnish European) in gnomAD v3.1.2 and a frequency of 0.000008792 (1/113744) in gnomAD v2.1.1, meeting criteria for PM2_Supporting. It has a REVEL score of 0.898 (PP3 is >0.6). One proband from PMID: 28300866 (family of four affected individuals), 2 probands from PMID: 15630491, 1 proband from PMID: 7989582, and 1 proband from PMID: 7795154 meet phenotype criteria for PS4, PP4 and PP1_Strong. Of note, PMID: 30005274 reports that the Asn219Asp variant associated with Type II RS is hardly detected by the different anti-FXa or anti-FIIa assay methods. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4, PP1_Strong, PP3, PP4, PM2_Supporting.

PP1_Strong

Four individuals from the same family with AT deficiency provides 3 conservative meioses meeting a supporting level. Two additional families were reported with relationships defined. Two segregations were counted in each of those families. Total = 7 segregations with at least one additional family reported.

PS4

2 probands from PMID: 15630491, 1 proband from PMID: 7989582, and 1 proband from PMID: 7795154 meets phenotype criteria for PS4. PS4 is applied based on 4 points.

PM2_Supporting

Asn219Asp missense variant is reported at a POPMAX FAF of 0.00000488 (non-Finnish European) in gnomAD v3.1.2 and a frequency of 0.000008792 (1/113744) in gnomAD v2.1.1, meeting criteria for PM2_Supporting

PP4

4 individuals from 1 family are noted to carry the Asn219Asp variant. Mean AT activity 72%, Ag 83%.

PP3

The c.655A>G (p.Asn219Asp) missense variant has a REVEL score of 0.898(>0.6).

PM5

Another variant, Asn219Lys is reported in the AT database, but is provisionally classified as VUS and does not meet PM5 criteria.

Curation History

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