ClinVar Miner

Submissions for variant NM_000506.5(F2):c.1787G>A (p.Arg596Gln)

dbSNP: rs387907201
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853373 SCV000996243 pathogenic Thrombophilia due to thrombin defect 2019-02-01 criteria provided, single submitter clinical testing This variant, referred to as the prothrombin Belgrade variant, has previously been reported in affected individuals with thrombophilia (PMID: 23265743, 23927452, 25550189, 26482463, 28075532). Functional assays indicate this substitution impairs binding of antithrombin to thrombin, leading to antithrombin resistance and a hypercoagulable state (PMID: 28075532, 27604259). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1787G>A (p.Arg596Gln) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1787G>A (p.Arg596Gln) variant is classified as pathogenic.
GeneDx RCV003156298 SCV003845757 pathogenic not provided 2022-09-22 criteria provided, single submitter clinical testing Published functional studies demonstrate antithrombin resistance and impaired thrombin-antithrombin complex formation, suggesting susceptibility to thrombosis (Takagi et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22716977, 25550189, 23265743, 26482463, 30279891, 29331940, 23927452, 28075532, 27604259, 33332610, 30428703, 30968704)
Labcorp Genetics (formerly Invitae), Labcorp RCV003514423 SCV004294776 pathogenic Congenital prothrombin deficiency 2024-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 596 of the F2 protein (p.Arg596Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant prothrombin-related thrombophilia (PMID: 28075532, 35945029). It has also been observed to segregate with disease in related individuals. This variant is also known as R553Q; prothrombin Belgrade mutation. ClinVar contains an entry for this variant (Variation ID: 692073). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt F2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects F2 function (PMID: 27604259). For these reasons, this variant has been classified as Pathogenic.

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