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.953C>T (p.Pro318Leu)

CA343774114

627161 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e12cc661-43a5-4e98-a4b1-600aab2e3f6e

HGVS expressions

NM_000488.4:c.953C>T

NM_000488.4(SERPINC1):c.953C>T (p.Pro318Leu)

NC_000001.11:g.173909752G>A

CM000663.2:g.173909752G>A

NC_000001.10:g.173878890G>A

CM000663.1:g.173878890G>A

NC_000001.9:g.172145513G>A

NG_012462.1:g.12627C>T

ENST00000367698.4:c.953C>T

ENST00000367698.3:c.953C>T

ENST00000487183.1:n.604C>T

ENST00000617423.4:c.559+2112C>T

NM_000488.3:c.953C>T

NM_001365052.1:c.809C>T

NM_001365052.2:c.809C>T

NM_001386302.1:c.1076C>T

NM_001386303.1:c.1034C>T

NM_001386304.1:c.932C>T

NM_001386305.1:c.896C>T

NM_001386306.1:c.737C>T

Pathogenic

PS4 PM2_Supporting PP4 PP3

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.953C>T variant predicts a Pro318Leu missense change. It is absent from gnomAD v2.1.1 and v3.1.2, meeting criteria for PM2_Supporting. It has a REVEL score of 0.956 and meets PP3 (threshold >0.6). At least 2 probands with AT deficiency (and repeat sampling) are reported in the literature (PP4) and 8 probands with AT deficiency and a positive family history are noted from internal VCEP data, meeting criteria for PS4_Very Strong. 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, PP3, PP4, PM2_Supporting.

PS4

10 Points | At least 1 additional proband not used for PP4 with AT deficiency (and repeat sampling) are reported in the literature, an individual with AT deficiency without mention of repeat sample and 8 probands with AT deficiency and a positive family history are noted from internal laboratory data, meeting criteria for PS4_VS.

PM2_Supporting

The variant is absent from gnomAD v2.1.1 and v3.1.2, meeting criteria for PM2_Supporting.

PP4

Case #41, female patient of Belgian or Spanish origin is reported with he Pro318Leu variant and AT deficiency. First thrombotic event was DVT at the age of 15yo, triggered by oral contraceptives. AT activity = 65% and AT antigen levels = 64%. Patient is noted to have Type II AT deficiency. Repeat sampling is noted.

PP3

The Pro318Leu missense variant has a REVEL score of 0.956 and meets PP3 (threshold >0.6)

Approved on: 2023-09-21

Published on: 2023-09-29

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