Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mayo Clinic Laboratories, |
RCV002284176 | SCV002573728 | pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing | PM1, PM2, PM5, PS3, PS4_moderate |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003330394 | SCV004038337 | pathogenic | Familial dysfibrinogenemia | 2023-08-07 | criteria provided, single submitter | clinical testing | Variant summary: FGA c.103C>T (p.Arg35Cys) 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 251232 control chromosomes. In a cross-sectional review of the literature, c.103C>T has been reported as the "A alpha Arg16Cys" variant in heterozygous or homozygous genotypes in multple individuals affected with features of Dysfibrinogenemia, some of whom reported multiple coagulation factor deficiencies (example, Galanakis_1993, Miesbach_2010, Preisler_2021). The inheritance of dysfibrinogemia is most often autosomal dominant with reports of severely affected homozygotes as well some variably affected heterozygotes and some reportedly asymptomatic heterozygotes. The range of phenotypes encountered can vary from undue bleeding, easy bruising to those experienced thrombotic events (Miesbach_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrating an impact on protein function was not ascertained in the context of this evaluation. The following publications have been ascertained in the context of this evaluation (PMID: 8457654, 15009465, 19923982, 33477601). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Prevention |
RCV003914851 | SCV004729647 | pathogenic | FGA-related condition | 2024-01-04 | criteria provided, single submitter | clinical testing | The FGA c.103C>T variant is predicted to result in the amino acid substitution p.Arg35Cys. This variant is also described using legacy nomenclature as p.Arg16Cys, has been reported to be causative for autosomal dominant dysfibrinogenemia in several families (Miesbach et al. 2010. PubMed ID: 19923982; Galanakis et al. 1993. PubMed ID: 8457654; Jiang et al. 2012. PubMed ID: 22967385). Other missense variants affecting amino acid residue p.Arg35 have also been reported in many patients with dysfibrinogenemia suggesting p.Arg35 is important for proper FGA protein function (see p.Arg35Ser Miesbach et al. 2010. PubMed ID: 19923982; p.Arg35His Soya et al. 2012. PubMed ID: 22880226; p.Ser35Pro Shapiro et al. 2013. PubMed ID: 23061815). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. |
| OMIM | RCV000017825 | SCV000038104 | pathogenic | Dysfibrinogenemia | 2006-07-01 | no assertion criteria provided | literature only |