Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000488.4(SERPINC1):c.529C>T (p.Arg177Cys)

CA1251403

529744 (ClinVar)

Gene: SERPINC1
Condition: antithrombin III deficiency
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 073335d6-5612-4a86-a192-a78286e4e9c9
Approved on: 2023-09-21
Published on: 2024-06-25

HGVS expressions

NM_000488.4:c.529C>T
NM_000488.4(SERPINC1):c.529C>T (p.Arg177Cys)
NC_000001.11:g.173911894G>A
CM000663.2:g.173911894G>A
NC_000001.10:g.173881032G>A
CM000663.1:g.173881032G>A
NC_000001.9:g.172147655G>A
NG_012462.1:g.10485C>T
ENST00000367698.4:c.529C>T
ENST00000367698.3:c.529C>T
ENST00000487183.1:n.234C>T
ENST00000617423.4:c.529C>T
NM_000488.3:c.529C>T
NM_001365052.1:c.385C>T
NM_001365052.2:c.385C>T
NM_001386302.1:c.529C>T
NM_001386303.1:c.610C>T
NM_001386304.1:c.529C>T
NM_001386305.1:c.529C>T
NM_001386306.1:c.409-1003C>T
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Uncertain Significance

Met criteria codes 2
BS1 PP3
Not Met criteria codes 2
BS3 PS4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Thrombosis VCEP
The c.529C>T (p.Arg177Cys) variant is reported at a POPMAX FAF of 0.001545 in the African/African American population in gnomAD v3.1.2, and is >BS1 cut-off of 0.0002. One proband in PMID: 28300866 and three probands from internal data with AT deficiency are noted to carry the variant ; however PS4 is not applied since BS1 is met. The variant has a REVEL score of 0.873, which exceeds the cutoff (>0.6) set by the VCEP. Thrombosis VCEP considers this variant as a variant of uncertain significance due to the presence of at least 4 cases with AT deficiency and a high REVEL score. While the population frequency is high, the absence of homozygotes in the population may argue against the variant being benign. The experimental evidence is unreliable with varying activity levels on different assays. A conservative approach would be to classify this variant as uncertain. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, PP3.
Met criteria codes
BS1
The c.529C>T (p.Arg177Cys) variant is reported at a POPMAX FAF of 0.001545 in the African/African American population in gnomAD v3.1.2, and is >BS1 cut-off of 0.0002.
PP3
REVEL score = 0.873 which exceeds our 0.6 cutoff
Not Met criteria codes
BS3
In PMID:33537542, Arg177Cys reported to show Ag level of ~57.4% and AT activity level of 105.3 (anti FXa s), 107.5 (anti-thrombin s), 60.5 (anti-FXa t), 61.7 (anti-thrombin t), when expressed in HEK293 cells.
PS4
1 proband with AT deficiency is noted to carry the variant in PMID: 28300866. Authors note that though the variant is present in population databases, they do not consider the frequency high enough and believe the variant is causative.
Curation History
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