Submissions for variant NM_000130.5(F5):c.1258G>T (p.Gly420Cys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003596845	SCV004293806	pathogenic	Congenital factor V deficiency	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 420 of the F5 protein (p.Gly420Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive factor V deficiency (PMID: 14511309, 15735820, 33858044, 33979974, 35946468). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as G1348T or Gly392Cys. 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) performed at Invitae indicates that this missense variant is expected to disrupt F5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects F5 function (PMID: 15735820). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003596845	SCV005395856	pathogenic	Congenital factor V deficiency	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: F5 c.1258G>T (p.Gly420Cys), also reported as Gly392Cys, results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251382 control chromosomes. c.1258G>T has been reported in the EAHAD Database (https://dbs.eahad.org/FV) and in the literature in the presumed compound heterozygous state in multiple individuals affected with autosomal recessive Congenital Factor V Deficiency (example, Guo_2021, Lin_2023, Zhang_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity in COS1 cells in vitro (example, Chen_2005). The following publications have been ascertained in the context of this evaluation (PMID: 15735820, 33858044, 35946468, 33979974). ClinVar contains an entry for this variant (Variation ID: 2734024). Based on the evidence outlined above, the variant was classified as pathogenic.