Submissions for variant NM_019616.4(F7):c.1093A>G (p.Met365Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690787	SCV005185941	uncertain significance	not specified	2024-05-03	criteria provided, single submitter	clinical testing	Variant summary: F7 c.1159A>G (p.Met387Val) results in a conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249394 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1159A>G has been reported in the literature in a heterozygous individual affected with Congenital factor VII deficiency (Herrmann_2009). This report does not provide unequivocal conclusions about association of the variant with Congenital factor VII deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 18976247). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004784215	SCV005397802	uncertain significance	Congenital factor VII deficiency	2024-05-17	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (A>G) at position 1159 of the coding sequence of the F7 gene that results in a methionine to valine amino acid change at residue 387 of the coagulation factor VII protein. This residue falls in the peptidase S1 domain of the protein (UniProt). This variant is absent from ClinVar and the published literature. This variant is present in 3/1613004 alleles (0.0006576%) in gnomAD v.4.1.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Met387 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PP2, PP3