Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001343327 | SCV001537297 | uncertain significance | Singleton-Merten syndrome 1; Aicardi-Goutieres syndrome 7 | 2020-10-03 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glycine at codon 924 of the IFIH1 protein (p.Glu924Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant has not been reported in the literature in individuals with IFIH1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. |
| Victorian Clinical Genetics Services, |
RCV004789538 | SCV005399379 | uncertain significance | Aicardi-Goutieres syndrome 7 | 2022-09-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Gain of function is a known mechanism of disease in this gene and is associated with Aicardi-Goutieres syndrome 7 (MIM#615846) (PMID 24686847) and Singleton-Merten syndrome 1 (MIM#182250) (PMID: 25620204). Loss of function is a known mechanism of disease in this gene and is associated with immunodeficiency 95 (MIM#619773, AR) (PMID: 29018476, 34185153). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated C-terminal domain RIG-1 (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The variant c.2770G>A; p.(Glu924Lys) has been reported as a variant of uncertain significance in ClinVar with limited clinical information provided. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in ClinVar once as a variant of uncertain significance with limited clinical information provided. (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |