Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000412805 | SCV000491268 | likely pathogenic | not provided | 2016-05-16 | criteria provided, single submitter | clinical testing | The L138F variant in the RNASEH2B gene has been reported previously in the compound heterozygous state in multiple unrelated individuals with Aicardi-Goutieres syndrome (Rice et al., 2007; La Piana et al., 2014; Rice et al., 2013). The L138F variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L138F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. Although in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function, RNASEH2B has a low rate of benign missense variation and missense variants are a common mechanism of disease (Stenson et al., 2014; Rice et al., 2007). Therefore, we interpret L138F as a likely pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Labcorp Genetics |
RCV000697138 | SCV000825733 | uncertain significance | Aicardi-Goutieres syndrome 2 | 2022-07-26 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 138 of the RNASEH2B protein (p.Leu138Phe). This variant is present in population databases (rs78705382, gnomAD 0.005%). This missense change has been observed in individuals with Aicardi-Goutières syndrome (AGS) and atypical AGS (PMID: 17846997, 25343331). ClinVar contains an entry for this variant (Variation ID: 372780). 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: "Deleterious"; PolyPhen-2: "Possibly 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. |