Submissions for variant NM_000488.4(SERPINC1):c.1157T>C (p.Ile386Thr)

dbSNP: rs1449772752

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Thrombosis Variant Curation Expert Panel, ClinGen	RCV001070670	SCV005061625	pathogenic	Hereditary antithrombin deficiency	2024-05-09	reviewed by expert panel	curation	The c.1157T>C (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 386 (p.Ile386Thr). This variants alters a conserved residue among the serpin superfamily located in the loop connecting two secondary structures (helix I with strand s5A). There is one allele present in gnomAD (NFE population) in v2.1.1 with a Popmax MAF <0.00002, which meets criteria for PM2_Supporting. The computational predictor REVEL gives a score of 0.752, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. This variant has been reported in at least 20 probands meeting an antithrombin activity level of <0.8 IU/mL and several more are reported in the literature (PS4_Very Strong >8 points proband count per Thrombosis VCEP guidelines). In addition, there is evidence to support this is a Founder variant in the Polish population (Weronska et al., 2023 PMID: 37021543) with a common haplotype defined by six additional SNVs. In addition, p.Ile386Thr causes an aberrant AT with slower electrophoretic mobility was observed in native Western blot gels, in comparison to three non-carriers. There is also evidence of increased clot lysis time in carriers of p.Ile386Thr with Type I deficiency (137 mins) when compared to healthy controls (~95 mins) suggesting a prothrombotic fibrin clot phenotype. Of note, crossed immunoelectrophoresis confirmed the mild type I deficiency without increased levels of forms with low heparin affinity (such as those seen in p.Arg79His). Finally, seven individuals from four families with mean AT heparin cofactor activity (COF) of 59% and AT antigen levels of 65% were reported in a French Cohort (Alhenc-Gelas et al., 2017; PMID: 28300866). Conservatively, we are counting three meiosis for application of PP1 in the absence of detailed pedigrees. In summary, based on the evidence available at this time, this is a pathogenic variant. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel Guidelines (Version 1.0.0) for AT Deficiency for SERPINC1 are PS4_VeryStrong, PM2_supporting, PP1, PP3 and PP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001070670	SCV001235934	likely pathogenic	Hereditary antithrombin deficiency	2022-04-24	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 863657). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 not expected to disrupt SERPINC1 protein function. This missense change has been observed in individuals with antithrombin III deficiency (PMID: 21264449, 28300866, 28607330, 29153735, 31157679, 33367661). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 386 of the SERPINC1 protein (p.Ile386Thr).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001070670	SCV001361601	pathogenic	Hereditary antithrombin deficiency	2021-08-23	criteria provided, single submitter	clinical testing	Variant summary: SERPINC1 c.1157T>C (p.Ile386Thr) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251466 control chromosomes (gnomAD). c.1157T>C has been reported in the literature in multiple individuals affected with Antithrombin Deficiency (Alhenc-Gelas_2010, Luxembourg_2011, Olivieri_2016, Gindele_2017, Wypasek_2017, Zabczyk_2021). These data indicate that the variant is very likely to be associated with disease. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV001070670	SCV004171580	pathogenic	Hereditary antithrombin deficiency	2023-11-24	no assertion criteria provided	clinical testing