Submissions for variant NM_000488.4(SERPINC1):c.439A>G (p.Thr147Ala)

gnomAD frequency: 0.00184  dbSNP: rs2227606

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Thrombosis Variant Curation Expert Panel, ClinGen	RCV001523260	SCV005061613	likely pathogenic	Hereditary antithrombin deficiency	2024-02-19	reviewed by expert panel	curation	The NM_000488.4(SERPINC1):c.439A>G variant predicts a missense change from Threonine to Alanine at position 147. Several patients with AT deficiency are reported with the Thr147Ala variant and meet the phenotype criteria for PS4_Very Strong and PP4. Reduced antithrombin activity was observed when the variant was analyzed by in in-vitro assays (PMID: 32920809) meeting PS3_Supporting. This variant has a frequency of 0.53% (>0.002 at 99.99% CI w/subpopulation of w/min of 5 alleles) in the African American subpopulation, with 143 heterozygous alleles (gnomAD v2.1.1). While this meets the BA1 cut-off set by the Thrombosis VCEP, the variant is excluded from the application from BA1 as it is a founder variant in the African population (PMID: 32920809). This missense variant has a REVEL score of 0.242, which is below the set threshold (>0.3), and meets BP4. However, the Thrombosis VCEP uses the Bayesian point system (PMID: 32720330) in the event of a variant meeting conflicting benign and pathogenic codes. In the case of Thr147Ala, PS4 is met at the very strong level. This give a total of 9 points, which corresponds to a likely pathogenic classification. In summary, the variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_VeryStrong, PP4, PS3_Supporting, BP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001523260	SCV001732934	benign	Hereditary antithrombin deficiency	2025-01-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003956212	SCV004773525	likely benign	SERPINC1-related disorder	2021-09-16	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).