Submissions for variant NM_000488.4(SERPINC1):c.391C>T (p.Leu131Phe)

gnomAD frequency: 0.00001  dbSNP: rs121909567

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Thrombosis Variant Curation Expert Panel, ClinGen	RCV000019650	SCV004037391	pathogenic	Hereditary antithrombin deficiency	2023-09-21	reviewed by expert panel	curation	The c.391C>T (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 131 (p.Leu131Phe; legacy nomenclature p.Leu99Phe, Antithrombin Budapest 3 (ATBp3)). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003516 (4/113752 alleles) in the non-Finnish European population, which does not meet criteria for PM2_Supporting (MAF =< 2.0 X 10-5 in gnomAD). The computational predictor REVEL gives a score of 0.853, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function (PP3). The variant has been reported to segregate with AT deficiency in at least 11 affected family members from 2 families (PP1_Strong; PMIDs: 32686144, 24072242). This variant has been reported in at least 100 probands with AT deficiency and is a founder variant in the Hugarian population. Further studies of the Hungarian cohort demonstrated that homozygosity was associated with thrombosis at a younger age and led to a high thrombotic risk while the heterozygous carriers also had venous and/or arterial thrombosis, as well as pregnancy complications. This variant was also reported in internal laboratory data (PS4_Very Strong; PMIDs: 26748602, 1555650, 32686144). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP1_strong, PP3, PS4_Very Strong
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000019650	SCV000899334	likely pathogenic	Hereditary antithrombin deficiency	2019-02-01	criteria provided, single submitter	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851769	SCV000899704	pathogenic	Deep venous thrombosis	2019-02-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000019650	SCV001380298	pathogenic	Hereditary antithrombin deficiency	2023-08-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 131 of the SERPINC1 protein (p.Leu131Phe). This variant is present in population databases (rs121909567, gnomAD 0.004%). This missense change has been observed in individuals with antithrombin deficiency (PMID: 22498748, 24072242, 24158114, 26748602). It has also been observed to segregate with disease in related individuals. This variant is also known as p.L99F. ClinVar contains an entry for this variant (Variation ID: 18034). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINC1 protein function. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 1555650, 22498748, 29215785).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001543498	SCV001762107	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000019650	SCV002515496	pathogenic	Hereditary antithrombin deficiency		criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000019650	SCV002581438	pathogenic	Hereditary antithrombin deficiency	2022-02-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000019650	SCV002810528	pathogenic	Hereditary antithrombin deficiency	2021-10-22	criteria provided, single submitter	clinical testing
OMIM	RCV000019650	SCV000039948	pathogenic	Hereditary antithrombin deficiency	1990-04-11	no assertion criteria provided	literature only
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000019650	SCV004041776	pathogenic	Hereditary antithrombin deficiency	2023-10-09	no assertion criteria provided	clinical testing