Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000518968 | SCV000621629 | uncertain significance | not provided | 2017-10-17 | criteria provided, single submitter | clinical testing | The I26N variant in the IFIH1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The I26N variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I26N as a variant of uncertain significance. |
Illumina Laboratory Services, |
RCV001249703 | SCV001423727 | uncertain significance | Aicardi-Goutieres syndrome 7 | 2020-03-09 | criteria provided, single submitter | clinical testing | The IFIH1 c.77T>A (p.Ile26Asn) variant is a missense variant, which resides in the CARD1 domain of IFIH1 (Rice et al. 2014). A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the limited evidence, the p.Ile26Asn variant is classified as a variant of unknown significance for Aicardi-Goutieres syndrome. |
Labcorp Genetics |
RCV001858039 | SCV002277239 | uncertain significance | Singleton-Merten syndrome 1; Aicardi-Goutieres syndrome 7 | 2023-06-23 | criteria provided, single submitter | clinical testing | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IFIH1 protein function. ClinVar contains an entry for this variant (Variation ID: 452793). This variant has not been reported in the literature in individuals affected with IFIH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 26 of the IFIH1 protein (p.Ile26Asn). |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003226318 | SCV003923169 | uncertain significance | not specified | 2023-03-24 | criteria provided, single submitter | clinical testing | Variant summary: IFIH1 c.77T>A (p.Ile26Asn) results in a non-conservative amino acid change located in the caspase recruitment domain (IPR031964) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251404 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.77T>A in individuals affected with Aicardi-Goutieres Syndrome 7 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |