MT-RNR1

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MT-RNR1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 4, 2024. The *MT-RNR1* gene encodes the mitochondrial ribosome 12S RNA subunit which is involved in mitochondrial translation. *MT-RNR1* was first reported in association with maternally inherited primary mitochondrial disease in 1993 (PMID: 7689398) in individuals with both aminoglycoside induced hearing loss and nonsyndromic hearing loss with no identifiable trigger. While various names have been given to the constellation of features seen in those with *MT-RNR1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT-RNR1* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting the gene-disease relationship between *MT-RNR1* and primary mitochondrial disease includes case-level data and experimental data. This curation included two variants (m.1555A>G and m.1494C>T) present in 12 probands from eight publications (PMIDs: 17698299, 16380089, 12920080, 24252789, 9490575, 8285309, 9040738, 7689389). Both these variants were reviewed by the ClinGen Mitochondrial Disease Variant Curation Expert Panel. The m.1555A>G variant is classified as pathogenic and m.1494C>T as likely pathogenic. Overall, the m.1555A>G variant has been reported in more than 65 individuals with primary mitochondrial disease, and the only consistent reported feature in affected individuals was hearing loss (PMIDs: 7689389, 1613771, 8285309, 8414970, 9111378, 9040738, 9490575, 9831149, 10661905, 12031626, 12920080, 16935512, 20123042, 22317974, 23357420, 24252789, 11870684). Some individuals with this variant have normal hearing, others have hearing loss following aminoglycoside exposure, and others have hearing loss and no known aminoglycoside exposure. Age of onset of hearing loss ranged from infancy (after aminoglycoside exposure) to adulthood. Hearing loss has been reported to be variable, stable in some individuals and progressive in others. Several reports of individuals receiving cochlear implants had good outcomes (PMIDs: 9831149, 16935512, 24252789). While most affected individuals have this variant present at homoplasmy, there have been some reports of heteroplasmic occurrences in those with hearing loss. There are isolated reports of individuals with this variant having other medical concerns, however there is not sufficient evidence currently that this variant was causative of these other problems. These problems include chronic progressive external ophthalmoplegia and myopathy (PMID: 11870684), cardiomyopathy (PMIDs: 28104394, 24252789), neural tube defect (PMID: 10661905), hypertension (PMID: 22317974), type 2 diabetes (PMID: 23357420), Parkinson disease (abstract only, Shoffner et al., 1996), autism spectrum disorder and intellectual disability (PMID: 29340697), and Leigh syndrome (PMID: 32867169). The m.1494C>T variant has been reported in >16 unrelated individuals with primary mitochondrial disease with non-syndromic hearing loss with and without aminoglycoside exposure. All were homoplasmic for the variant with the exception of one case who was heteroplasmic at 85.1% in blood (PMIDs: 34467602, 20100600, 17084680, 16380089, 17434445, 17698299, 17698030, 30693673, 14681830). Several studies in patient cells (PMIDs: 8817331, 9915970), cybrids (PMIDs: 8687424, 11230176. 15722487), and single fiber testing (PMID: 9915970) support the functional impact of these variants. Additional variants in this gene have been reported to be associated with primary mitochondrial disease, however insufficient clinical detail was provided and/or there was a lack of comprehensive analyses excluding other causes, therefore these additional variants were not included in this curation (m.827A>G – PMIDs: 16650816, 16782057, 18261986; m.961delTinsC - PMIDs: 7550368, 10326749; m.1027A>G – PMIDs: 23328039, 21205314, 20100600; m.1095T>C – PMIDs: 11313749, 11079536, 15637703). This gene-disease association is also supported by known biochemical function (PMID: 33340416). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 4, 2024 (SOP Version 10).