Submissions for variant NM_019616.4(F7):c.1025G>A (p.Arg342Gln)

gnomAD frequency: 0.00118  dbSNP: rs121964926

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479479	SCV000568816	pathogenic	not provided	2023-02-08	criteria provided, single submitter	clinical testing	Published studies demonstrate most individuals exhibit prolonged prothrombin times (PT) and F7 activity below 10% using rabbit brain thromboplastin, but normal PT and F7 activity using ox brain thromboplastin and intermediate values with human brain thromboplastin, while purified FVII protein from one individual homozygous for R364Q exhibited no detectable FVII clotting activity (O'Brien et al., 1991; Kirkel et al., 2010); Also known as R304Q and F7-Padua; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 2070047, 20958793, 8242057, 8043443, 22995991, 18976247, 8883260, 15590402, 34598035, 32472540, 34342048, 21902896, 24711753, 12903033, 11313743, 1634227, 15970722, 10959697, 22873696, 20040857, 25828579, 26105150, 25863091, 34426522)
Eurofins Ntd Llc (ga)	RCV000479479	SCV000857897	other	not provided	2017-10-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779130	SCV000915625	pathogenic	Factor VII deficiency	2018-10-23	criteria provided, single submitter	clinical testing	The F7 c.1091G>A (p.Arg364Gln) missense variant, also commonly referred to in the literature as p.Arg304Gln or the "Pauda" variant, has been reported in at least eight studies in which it is identified in at least 70 individuals, including 11 clinically symptomatic homozygotes and two clinically symptomatic compound heterozygotes (Ding et al. 2003; Marty et al. 2008; Girolami et al. 2011; Rabelo et al. 2015). The p.Arg364Gln variant has also been reported in at least 19 clinically asymptomatic homozygotes with lower factor VII activity than wildtype (O'Brien et al. 1991; Girolami et al. 2011; Rabelo et al. 2015). The variant is present at a frequency of 0.00908 in the African population of the 1000 Genomes Project. This allele frequency is high but may be consistent with disease prevalence and the fact that many individuals with factor VII deficiency are clinically asymptomatic. Girolami et al. (2011) found the mean levels of activated FVII in six homozygotes to be significantly lower than the activated FVII levels in 21 normal controls. Further, the variant was associated with reduced factor VII activity when assayed with rabbit brain thromboplastin, however, the activity levels varied between the use of human placenta, recombinant human or ox-brain thromboplastin (O'Brien et al. 1991; Kirkel et al. 2010; Girolami et al. 2011; Girolami et al. 2011; Rabelo et al. 2015). Based on the collective evidence, the p.Arg364Gln variant is classified as a pathogenic risk factor for factor VII deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000779130	SCV001448741	pathogenic	Factor VII deficiency	2018-07-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003147479	SCV002024556	likely pathogenic	Congenital factor VII deficiency	2020-10-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496859	SCV002812402	pathogenic	Myocardial infarction, susceptibility to; Congenital factor VII deficiency	2022-04-12	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV003147479	SCV004013121	pathogenic	Congenital factor VII deficiency		criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003419797	SCV004115092	pathogenic	F7-related condition	2023-08-12	criteria provided, single submitter	clinical testing	The F7 c.1091G>A variant is predicted to result in the amino acid substitution p.Arg364Gln. This variant has been reported to be causative for autosomal recessive factor VII deficiency in several patients with varying clinical phenotypes ranging from asymptomatic to mild bleeding or severe bleeding after trauma (Girolami et al. 2011. PubMed ID: 21902896; Kirkel et al. 2010. PubMed ID: 20040857; O’Brien et al. 1991. PubMed ID: 2070047). Most patients with the p.Arg364Gln variant showed prolonged prothrombin times (PT); however, PT results using F7 protein with this variant are variable – ranging from severely reduced to normal – depending upon the source of substrate used for the biochemical test (O’Brien et al. 1991. PubMed ID: 2070047; Cristiani et al. 2013. PubMed ID: 24711753). The p.Arg364Gln substitution does not appear to alter F7 protein levels, rather, it appears to alter substrate binding (see for example O’Brien et al. 1991. PubMed ID: 2070047; Cristiani et al. 2013. PubMed ID: 24711753). Other substitutions of amino acid p.Arg364 have been reported in patients with Factor VII deficiency (e.g. p.Arg364Trp, Matsushita et al. 1994. PubMed ID: 8125953, Cristiani et al. 2013. PubMed ID: 24711753) suggesting that amino acid residue p.Arg364 is important for proper F7 protein function. Given all the evidence, we interpret c.1091G>A (p.Arg364Gln) as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000479479	SCV004135698	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	F7: PS4, PM3, PM5, PM2:Supporting, PS3:Supporting
Mayo Clinic Laboratories, Mayo Clinic	RCV000479479	SCV004224439	pathogenic	not provided	2023-01-20	criteria provided, single submitter	clinical testing	PM3_strong, PM5, PS3, PS4_moderate
OMIM	RCV001843424	SCV000033088	pathogenic	Factor VII Padua	1992-07-01	no assertion criteria provided	literature only