Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000000683 | SCV000915367 | pathogenic | Factor V deficiency | 2019-01-11 | criteria provided, single submitter | clinical testing | The F5 c.5189A>G (p.Tyr1730Cys) missense variant, also referred to as p.Tyr1702Cys in the literature, has been reported in four studies in which it is found in a total of seven individuals with factor V deficiency and FV:C levels <1-2%, including in four in a homozygous state, in two in a compound heterozygous state, and in one in a heterozygous state in whom a second variant was not identified (Castoldi et al. 2001; Montefusco et al. 2003; Yamakage et al. 2006; Talbot et al. 2010). Two of the homozygous individuals remained asymptomatic. The p.Tyr1730Cys variant is also found in three symptomatic individuals with FV:C levels of between 30-60%, including one individual with digenic variants (Castoldi et al. 2000; Castoldi et al. 2001). The p.Tyr1730Cys variant was reported in one of 200 control individuals who showed reduced FV levels (FV:c 58%). This variant is reported at a frequency of 0.000036 in the European (non-Finnish) population of the Genome Aggregation Database. Castoldi et al. (2000) noted a lack of expression of the p.Tyr1730Cys variant protein in the plasma of an affected individual while FV activity in plasma of carriers was reported at 65% (Yamakage et al. 2006). Additionally, functional studies in COS-1 cells demonstrate significantly impaired secretion and inadequate FV procoagulant activity of mutant protein as compared to the wildtype protein (Yamakage et al. 2006). The Tyr1730 residue is highly conserved and X-ray crystal structure analysis suggest that this residue may play an important role in maintaining the structure and function of the FV molecule. Based on the collective evidence the p.Tyr1730Cys variant is classified as pathogenic for factor V deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Labcorp Genetics |
RCV003595850 | SCV004293796 | pathogenic | Congenital factor V deficiency | 2023-09-03 | criteria provided, single submitter | clinical testing | This variant is also known as p.Tyr1702Cys. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 649). This missense change has been observed in individual(s) with factor V deficiency (PMID: 10942390, 11418372, 16476093, 24517203). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs118203907, gnomAD 0.004%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1730 of the F5 protein (p.Tyr1730Cys). |
| Gene |
RCV004766973 | SCV005376938 | likely pathogenic | not provided | 2024-04-18 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: significantly decreased protein level and activity (PMID: 16476093); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.5279A>G p.Y1702C; This variant is associated with the following publications: (PMID: 11435304, 11418372, 12816860, 20735394, 24517203, 16476093, 10942390) |
| OMIM | RCV000000683 | SCV000020833 | pathogenic | Factor V deficiency | 2001-07-15 | no assertion criteria provided | literature only |