Submissions for variant NM_000130.5(F5):c.1321C>T (p.Arg441Cys)

gnomAD frequency: 0.00002  dbSNP: rs747006175

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000778946	SCV000899477	likely pathogenic	Factor V deficiency	2019-02-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000778946	SCV000915368	uncertain significance	Factor V deficiency	2018-12-05	criteria provided, single submitter	clinical testing	The F5 c.1321C>T (p.Arg441Cys) missense variant has been reported in two studies in which it is found in two individuals affected with factor V deficiency, including one each in a compound heterozygous and heterozygous state (Jin et al. 2009; Delev at al. 2009). The proband reported in Jin et al. (2009) inherited the p.Arg441Cys variant from his unaffected mother and the second missense variant from his unaffected father. The proband's unaffected child was also heterozygous for the p.Arg441Cys variant. Control data are unavailable for this variant, which is reported at a frequency of 0.000239 in the European (Finnish) population of the Genome Aggregation Database. Based on the limited evidence, the p.Arg441Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for factor V deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003992386	SCV004809705	uncertain significance	Thrombophilia due to activated protein C resistance	2024-04-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003908080	SCV004726142	likely pathogenic	F5-related disorder	2023-10-24	no assertion criteria provided	clinical testing	The F5 c.1321C>T variant is predicted to result in the amino acid substitution p.Arg441Cys. This variant has been reported in the compound heterozygous state with another missense variant in a patient with moderate Factor V deficiency (described as C1321T (Arg413Cys) in Jin et al. 2009. PubMed ID: 19900106). The proband’s unaffected mother and unaffected son were both heterozygous for the p.Arg441Cys variant. This variant was also observed in the heterozygous state (in the absence of a second plausible causative variant) in one patient referred for genetic analysis due to either bleeding or asymptomatic mild/borderline factor V deficiency detected during routine coagulation testing (described as Arg413Cys in Delev et al. 2009. PubMed ID: 19486170) and in a second patient with a bleeding, thrombotic, or platelet disorder (Downes et al. 2019. PubMed ID: 31064749). We have also observed this variant at PreventionGenetics in a trans configuration with other pathogenic variants in patients with factor V deficiency. We interpret this variant as likely pathogenic.