Submissions for variant NM_019616.4(F7):c.1325del (p.Pro442fs)

dbSNP: rs750457207

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851926	SCV000899306	likely pathogenic	Factor VII deficiency	2019-02-01	criteria provided, single submitter	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851695	SCV000899495	likely pathogenic	Abnormal bleeding	2019-02-01	criteria provided, single submitter	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000851926	SCV001368368	likely pathogenic	Factor VII deficiency	2019-09-11	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001091745	SCV002051599	likely pathogenic	not provided	2021-02-25	criteria provided, single submitter	clinical testing	PVS1, PM2
Mayo Clinic Laboratories, Mayo Clinic	RCV001091745	SCV002573748	pathogenic	not provided	2024-07-16	criteria provided, single submitter	clinical testing	PP5, PM2_moderate, PM4, PS3, PS4_moderate
Fulgent Genetics, Fulgent Genetics	RCV002507337	SCV002811015	likely pathogenic	Myocardial infarction, susceptibility to; Congenital factor VII deficiency	2024-03-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001091745	SCV004034619	pathogenic	not provided	2023-03-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result as the last 3 amino acids are replaced with 31 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 24533960, 29618153, 31064749, 29246447, 22180436, 7919338)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002245647	SCV005086175	pathogenic	Congenital factor VII deficiency	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with factor VII deficiency (MIM#227500) and myocardial infarction, decreased susceptibility to (MIM#608446). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Patients with the same genotype have been observed with phenotypes ranging from asymptomatic to symptomatic (PMID: 18976247). (I) 0208 - Variant is predicted to result in an elongated protein. (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (18 heterozygotes, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable PTC variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in many individuals homozygote for this variant in cis with p.(Ala332Val), and in compound heterozygote individuals, with reduced FVII activity. It has also been reported as pathogenic and likely pathogenic in ClinVar (PMID: 18976247). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000851926	SCV000033100	pathogenic	Factor VII deficiency	1994-10-01	no assertion criteria provided	literature only
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002245647	SCV002515629	pathogenic	Congenital factor VII deficiency		no assertion criteria provided	research
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV002245647	SCV004099300	pathogenic	Congenital factor VII deficiency	2023-10-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004753032	SCV005353553	pathogenic	F7-related disorder	2024-03-15	no assertion criteria provided	clinical testing	The F7 c.1391delC variant is predicted to result in a frameshift and premature protein termination (p.Pro464Hisfs*32). This variant, previously described as p.Pro404Hisfs*32 using legacy nomenclature, has been reported to be causative for Factor VII Deficiency, and to our knowledge, has always been reported in a cis configuration (i.e. on the same allele) with the c.1061C>T (p.Ala354Val) variant described above in this patient (Arbini et al. 1994. PubMed ID: 7919338; Batorova et al. 2014. PubMed ID: 24533960). Functional in vitro studies have shown that the p.Pro464Hisfs*32 variant results in inefficient secretion from the endoplasmic reticulum (Andersen et al. 2018. PubMed ID: 29618153; Chollet et al. 2018. PubMed ID: 29246447). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/). Frameshift variants in F7 are expected to be pathogenic. This variant is interpreted as pathogenic.