Submissions for variant NM_000488.4(SERPINC1):c.1121A>G (p.Asp374Gly)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetics and Molecular Pathology, SA Pathology	RCV003447783	SCV004175529	uncertain significance	Hereditary antithrombin deficiency	2023-07-19	criteria provided, single submitter	clinical testing	The SERPINC1 c.1121A>G variant is classified as a VUS (PS4_Supporting, PM2, PP3) The SERPINC1 c.1121A>G variant is a single nucleotide change in exon 5/7 of the SERPINC1 gene, which is predicted to change the amino acid aspartic acid at position 374 in the protein to glycine. The variant has been reported in a patient with Antithrombin deficiency (PMID:22398878) (PS4_Supporting). This variant is absent from population databases (PM2). An additional patient with antithrombin deficiency has also been reported at this residue (p.Asp374Val)(Aslan et al 2021, PMID: 33401890). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in the HGMD database: CM125929. It has not been reported in dbSNP or ClinVar.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003447783	SCV005731059	uncertain significance	Hereditary antithrombin deficiency	2024-04-14	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 374 of the SERPINC1 protein (p.Asp374Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of antithrombin III deficiency (PMID: 22398878; Invitae). ClinVar contains an entry for this variant (Variation ID: 2664808). 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 80%. This variant disrupts the p.Asp374 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been observed in individuals with SERPINC1-related conditions (PMID: 33401890), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.