RNASEH2C was first reported in relation to autosomal recessive Aicardi-Goutieres type 3 (OMIM: 610330) in 2006 (PMID: 16845400). RNASEH2C encodes ribonuclease H2 subunit C, which comprises 164 amino acids. RNASEH enzymes endolytically cleave ribonucleotides from RNA:DNA duplexes, which occur during DNA replication, transcription and translation. RNASEH2 has been proposed to function in the removal of lagging strand Okazaki fragment RNA primers during DNA replication, as well as in the excision of single ribonucleotides from DNA:DNA duplexes (PMIDs: 21177854, 16845400).
The described autosomal recessive RNASEH2C phenotype is considered to be a form of type 1 interferonopathy, which is defined as a condition in which increased type 1 interferon signaling leads to autoimmune and neurological disorders (MONDO: 0700258). These disorders are caused by variants in genes involved in nucleic acid metabolism, sensing, and the innate immune response. Individuals with biallelic variants in RNASEH2C can present with a range of symptoms of variable severity and age of onset, within the context of an autoimmune disease.
At least 16 unique variants (missense, splicing, nonsense, indel) have been reported across 15 probands in 7 publications (PMIDs: 31130681, 23322642, 35551623, 16845400, 31559893, 25604658, 24183309) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is thought to be loss of function. This gene-disease relationship is also supported by experimental evidence (model system studies, PMID: 22802351). Although the mouse phenotype was limited due to early embryonic lethality, cells obtained from knock-out mouse embryos demonstrated increased genomic ribonucleotide load consistent with the underlying disease mechanism for type 1 interferonopathy (PMID: 22802351).
In summary, there is definitive evidence supporting the relationship between RNASEH2C and autosomal recessive RNASEH2C-related type 1 interferonopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic setting, and has been upheld over time. This classification was approached by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date July 10, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.