Submissions for variant NM_000488.4(SERPINC1):c.235C>T (p.Arg79Cys)

gnomAD frequency: 0.00005  dbSNP: rs121909547

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Thrombosis Variant Curation Expert Panel, ClinGen	RCV000019620	SCV005061615	pathogenic	Hereditary antithrombin deficiency	2024-02-19	reviewed by expert panel	curation	The c.235C>T (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 79 (p.Arg79Cys). This variant has been reported in at least 31 probands meeting an antithrombin activity level of <0.8 IU/mL and several more are reported in the literature (PS4_Very Strong; PMID:28300866). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in 18 affected family meioses from 32 families (PP1_Strong; 28300866). One of 50 individuals within 45 families who had a mean AT activity of 53% and AT antigen level of 106%, which is highly specific for hereditary antithrombin deficiencies. The curators confirmed with lead author that most individuals AT levels were confirmed with at least two samples since this is not specified in the publication. The ClinGen Thrombosis VCEP members have agreed that all probands in this paper can be counted at full strength for PP4 (PP4_Supporting; PMID:28300866). The computational predictor REVEL gives a score of 0.743, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant resides within a region, Arg79, of SERPINC1 that would impact heparin binding site residues and is defined as a critical functional domain by the ClinGen Thrombosis VCEP (PMID:2615648; PM1). Another missense variant c.236G>A (p.Arg79His) (ClinVarID:18014) in the same codon has been classified as pathogenic for autosomal dominant hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PS4_Very strong, PM1, PM5, PP3, PP4. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval)
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000019620	SCV000899613	likely pathogenic	Hereditary antithrombin deficiency	2019-02-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000019620	SCV001391190	pathogenic	Hereditary antithrombin deficiency	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the SERPINC1 protein (p.Arg79Cys). This variant is present in population databases (rs121909547, gnomAD 0.02%). This missense change has been observed in individuals with antithrombin III deficiency (PMID: 3960724, 6582486, 21325262, 24162787, 25837307, 28300866). It has also been observed to segregate with disease in related individuals. This variant is also known as R47C, Arg47Cys, Antithrombin III Toyama, Antithrombin III Alger, and Antithrombin III tours. ClinVar contains an entry for this variant (Variation ID: 18004). 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 with a negative predictive value of 95%. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 22498748, 27322195). This variant disrupts the p.Arg79 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2615648, 3567355, 7981186, 21264449, 25837307, 26748602, 28607330, 29153735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000019620	SCV002059060	likely pathogenic	Hereditary antithrombin deficiency	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000018004, PMID:6582486, PS1_S). A different missense change at the same codon has been reported to be associated with SERPINC1 related disorder (ClinVar ID: VCV000018015, PMID:2615648,3350974, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.743, PP3_P). A missense variant is a common mechanism associated with Thrombophilia due to antithrombin III deficiency (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000048, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000019620	SCV002499590	likely pathogenic	Hereditary antithrombin deficiency		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV004791230	SCV005414061	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
OMIM	RCV000019620	SCV000039918	pathogenic	Hereditary antithrombin deficiency	1996-01-01	no assertion criteria provided	literature only