Submissions for variant NM_000488.4(SERPINC1):c.536T>C (p.Phe179Ser)

dbSNP: rs483352847

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Thrombosis Variant Curation Expert Panel, ClinGen	RCV000818141	SCV005061628	uncertain significance	Hereditary antithrombin deficiency	2024-01-25	reviewed by expert panel	curation	The c.536T>C (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 179 (p.Phe179Ser). The variant is absent from gnomAD v2.1.1 and v3.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting. The computational predictor REVEL gives a score of 0.946, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: PP3, PM2_Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818141	SCV000958739	likely pathogenic	Hereditary antithrombin deficiency	2020-01-03	criteria provided, single submitter	clinical testing	This variant disrupts the p.Phe179 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been observed in individuals with SERPINC1-related conditions (PMID: 16705712, 15164384, 28317092), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt SERPINC1 protein function. This variant has been observed in individual(s) with SERPINC1-related conditions (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with serine at codon 179 of the SERPINC1 protein (p.Phe179Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine.