Submissions for variant NM_000488.4(SERPINC1):c.1315C>A (p.Pro439Thr)

gnomAD frequency: 0.00001  dbSNP: rs1487411568

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Thrombosis Variant Curation Expert Panel, ClinGen	RCV003330321	SCV004037396	pathogenic	Hereditary antithrombin deficiency	2023-09-21	reviewed by expert panel	curation	The c.1315C>A (p.Pro439Thr) variant is reported at an MAF of (FAF not available), 1/68048 alleles in the non-Finnish European population in gnomAD v3.1.1 and meets criteria for PM2_Supporting (threshold <0.00002). It has a REVEL score of 0.88 and meets criteria for PP3. Several probands can be counted across the literature, who meet phenotype criteria for AT deficiency with a mix of repeat sampling, meeting PP4 and PS4. Four segregations are counted across two families meeting criteria for PP1_Moderate. Expression of mutant AT, 439Thr-AT, in HEK293 cells described in PMID: 18480576 revealed decrease in AT secretion, meeting criteria for PS3_Supporting. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4, PP1_Moderate, PP3, PP4, PM2_Supporting, PS3_Supporting.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852017	SCV000899475	likely pathogenic	Abnormal thrombosis	2019-02-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV003330321	SCV004293828	pathogenic	Hereditary antithrombin deficiency	2023-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 439 of the SERPINC1 protein (p.Pro439Thr). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro439 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16705712, 23910795, 28300866; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 18480576). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SERPINC1 protein function. ClinVar contains an entry for this variant (Variation ID: 627228). This variant is also known as P407T. This missense change has been observed in individual(s) with antithrombin III deficiency (PMID: 1469094, 24814625, 28229161, 29153735, 31030036, 31064749).