Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Knight Diagnostic Laboratories, |
RCV000454272 | SCV000538028 | pathogenic | Congenital afibrinogenemia | 2015-09-26 | criteria provided, single submitter | clinical testing | The c.502C>T, p.Arg168ter variant has been seen in the homozygous state in four individuals: one Norwegian (Fellowes et al., 2000) and three Sardinian (Asselta et al., 2001), who were diagnosed with congenital afibrinogenemia. All these individuals had immunologically very low; to undetectable fibrinogen levels suggesting that loss-of-function is a mechanism of disease. Furthermore, this variant was shown to co-segregate with disease and family members who were heterozygous for this variant were unaffected (Fellowes et al., 2000). Arginine at position 168 is evolutionarily conserved and it is present within the coil-coil domain of the protein. This domain is critical for protein assembly. Indeed, an in vitro study using the p.Arg168ter variant showed an absence of secreted fibrinogen because of its inability to assemble with the other fibrinogen subunits (β and γ) (Asselta et al., 2001). This variant is either absent or present at a very low frequency, with no homozygotes, in the population databases (1000 Genome, Exome Sequencing Project and ExAC). In summary, this variant meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing. |
| Invitae | RCV001380954 | SCV001579186 | pathogenic | not provided | 2017-07-06 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Analysis of patient-derived plasma was unable to detect fibrinogen via clotting and immunological methods in an individual carrying this variant along with another rare FGA variant (PMID: 26763372). This variant has been reported in the homozygous or compound heterozygous state in individuals affected with afibrinogenaemia (PMID: 10887149, 26763372). ClinVar contains an entry for this variant (Variation ID: 402230). This variant is present in population databases (rs755117226, ExAC 0.001%). This sequence change results in a premature translational stop signal in the FGA gene (p.Arg168*). This is expected to delete the last 477 amino acids (~74%) of the FGA protein. |
| Fulgent Genetics, |
RCV002502594 | SCV002805160 | pathogenic | Familial visceral amyloidosis, Ostertag type; Congenital afibrinogenemia; Familial dysfibrinogenemia | 2021-08-02 | criteria provided, single submitter | clinical testing |