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

CA210779

18030 (ClinVar)

Gene: SERPINC1

Condition: antithrombin III deficiency

Inheritance Mode: Autosomal dominant inheritance

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: PM2_Supporting PP3 PS4_Very Strong

• Not Met criteria codes: PP1

Expert Panel

Thrombosis VCEP

Criteria Specification Information

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

• 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).
• 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.
• 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