Submissions for variant NM_000488.4(SERPINC1):c.1141T>C (p.Ser381Pro)

dbSNP: rs121909565

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Thrombosis Variant Curation Expert Panel, ClinGen	RCV000019648	SCV005442757	uncertain significance	Hereditary antithrombin deficiency	2024-12-20	reviewed by expert panel	curation	The c.1141T>C variant in SERPINC1 is a missense variant predicted to cause substitution of serine by proline at amino acid 381 (p.Ser381Pro). This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL. Only one had a family history of disease supported with reported antithrombin activity levels (PS4_Supporting; PMIDs: 1551681, 30975910). The variant has been reported to segregate with hereditary antithrombin deficiency in two affected meioses from one family (PP1; PMID:1551681). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.616, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PP3, PM2_Supporting, PS4_Supporting. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000019648	SCV004293834	likely pathogenic	Hereditary antithrombin deficiency	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 381 of the SERPINC1 protein (p.Ser381Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant antithrombin deficiency (PMID: 1551681, 30975910). It has also been observed to segregate with disease in related individuals. This variant is also known as Ser349Pro. ClinVar contains an entry for this variant (Variation ID: 18032). 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.Ser381 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been observed in individuals with SERPINC1-related conditions (PMID: 29153735), 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.
OMIM	RCV000019648	SCV000039946	pathogenic	Hereditary antithrombin deficiency	1992-03-01	no assertion criteria provided	literature only