Submissions for variant NM_000130.5(F5):c.436C>T (p.Arg146Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764221	SCV004521042	pathogenic	Congenital factor V deficiency	2022-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg146*) in the F5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in F5 are known to be pathogenic (PMID: 30924984). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with F5-related conditions. This variant is present in population databases (rs767477438, gnomAD 0.003%).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003764221	SCV004848734	likely pathogenic	Congenital factor V deficiency	2022-08-26	criteria provided, single submitter	clinical testing	The p.Arg146X variant in F5 has not been previously reported in individuals with Factor V deficiency and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 136, which is predicted to lead to a truncated or absent protein. Loss of function of the F5 gene is an established disease mechanism in autosomal recessive Factor V deficiency. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Factor V deficiency. ACMG/AMP criteria applied: PVS1, PM2_Supporting.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003764221	SCV005398691	pathogenic	Congenital factor V deficiency	2022-09-02	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: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function leads to factor V deficiency (MIM#227400), whereas gain of function is associated with thrombophilia due to activated protein C resistance (MIM#188055) (PMID: 30297698). (I) 0108 - This gene is associated with both recessive and dominant disease. Factor V deficiency (MIM# 227400) is inherited in a recessive manner, however thrombophilia due to activated protein C resistance (MIM#188055) is autosomal dominant, although the risk is increased when recessive inheritance occurs. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign