Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001064935 | SCV001229872 | uncertain significance | Singleton-Merten syndrome 1; Aicardi-Goutieres syndrome 7 | 2023-12-25 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 854 of the IFIH1 protein (p.Met854Arg). This variant is present in population databases (rs138373022, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with IFIH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 858942). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt IFIH1 function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Met854 amino acid residue in IFIH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29270977). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |