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]
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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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  • No CSPEC computed assertion could be determined for this classification!
  • See Evidence submitted by expert panel for details.

Variant: NM_000488.4(SERPINC1):c.482G>A (p.Arg161Gln)

CA210779

18030 (ClinVar)

Gene: SERPINC1
Condition: antithrombin III deficiency
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8dce18fe-3323-4d15-b3de-da6f74c95ef9
Approved on: 2024-07-03
Published on: 2024-09-30

HGVS expressions

NM_000488.4:c.482G>A
NM_000488.4(SERPINC1):c.482G>A (p.Arg161Gln)
NC_000001.11:g.173911941C>T
CM000663.2:g.173911941C>T
NC_000001.10:g.173881079C>T
CM000663.1:g.173881079C>T
NC_000001.9:g.172147702C>T
NG_012462.1:g.10438G>A
ENST00000367698.4:c.482G>A
ENST00000367698.3:c.482G>A
ENST00000487183.1:n.187G>A
ENST00000617423.4:c.482G>A
NM_000488.3:c.482G>A
NM_001365052.1:c.338G>A
NM_001365052.2:c.338G>A
NM_001386302.1:c.482G>A
NM_001386303.1:c.563G>A
NM_001386304.1:c.482G>A
NM_001386305.1:c.482G>A
NM_001386306.1:c.409-1050G>A

Pathogenic

Met criteria codes 3
PP3 PM2_Supporting PS4_Very Strong
Not Met criteria codes 1
PP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Thrombosis VCEP
The c.482G>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 161 (p.Arg161Gln also known as ATIII Geneva). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008790 (1/113762 alleles) in the European population, which is lower than the ClinGen SERPINC1 threshold ([<0.00002]) for PM2_supporting, and therefore meets this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.691, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. The variant has been reported in at least 9 probands with AT deficiency in the literature meeting PS4_very strong (9 points applied PMID 28300866, 2229057, 3603409). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PM2_supporting, PP3, PS4_very strong.
Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.691, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3.
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008790 (1/113762 alleles) in the European population, which is lower than the ClinGen SERPINC1 threshold ([<0.00002]) for PM2, and therefore meets this criterion (PM2_supporting).
PS4_Very Strong
The variant has been reported in at least 9 probands with AT deficiency in the literature (9 points applied PMID 28300866, PMID 2229057, PMID 3603409).
Not Met criteria codes
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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