ClinVar

Description

The m.1494C>T variant in MTRNR1 has been reported in the homoplasmic state in >20 Asian and 2 Spanish probands with hearing loss ranging from mild to profound, with the majority having reported exposure to aminoglycoside antibiotics (Zhao 2004 PMID: 14681830, Wang 2006 PMID: 16380089, Rodriguez-Ballesteros 2006 PMID: 17085680, Chen 2007 PMID: 17698299, Han 2007 PMID: 17434445, Zhu 2009 PMID: 19682603, Lu 2010 PMID: 20100600, Shen 2011 PMID: 21205314, Ding 2016 PMID: 27397648, Zhou 2019 PMID: 30693673). Additionally, this variant segregated with hearing loss in many matrilineal relatives; however, a number of matrilineal relatives with the variant were not reported to have hearing loss with an average penetrance of 18% (range 0-77%) among different families (Barbarino 2016 PMID: 27654872). Most of these non-penetrant relatives were reported to not have aminoglycoside exposure. Additionally, a meta-analysis of case-control and cohort studies identified the variant at a higher frequency in patients with hearing loss who had been treated with aminoglycosides compared to untreated patients with hearing loss (1.1% vs. 0.056%, respectively, p=0.001). Furthermore, the meta-analysis also found that the m.1494C>T variant was associated with hearing loss and aminoglycoside treatment compared with controls (OR = 2.47 (1.04 - 3.91), p=0.001). The 1494T variant was also significantly associated with hearing loss independent of aminoglycoside use ( OR=1.19 (0.18-2.19), p=0.02). However, it should be noted that the confidence interval crossed or was close to 1 (Jing 2015). This variant was classified as Likely Pathogenic on Jul 11, 2022 by the ClinGen-approved Mitochondrial disease expert panel (Variation ID: 9632). This variant is also reported in ClinVar by PharmGKB with evidence level 2B, indicating moderate level of an association for variant-drug combination; however without statistical significance and/or small effect sizes. This variant has also been reported in 16% (1/6) of samples from haplogroup A6a, 0.84% (2/239) of samples from haplogroup D4j, and 0.08% (1/1202) of samples from haplogroup J1c (MitoMap; https://www.mitomap.org/MITOMAP). In addition, this variant has been reported in 0.067% (1/1493) of South Asian and 0.039% (10/25849) of European chromosomes in the homoplasmic state by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). The nucleotide position at m.1494 is highly conserved through species. It is predicted to form a novel U1494-1555A base pair which is in the same position as the C1494-1555G pair which is a known cause of hearing loss. In vitro functional studies in cyrbrids provide some evidence that this variant shows decrease in transcription and mitochondrial protein synthesis in both symptomatic and asymptomatic individuals (Zhao 2005 PMID: 15722487). In summary, while further case-control studies are required to determine the effect size of this allele, the current data supports a classification of likely pathogenic for hearing loss, especially in the context of exposure to aminogylosides. ACMG/AMP Criteria applied: PS4, PM5, PS3_Supporting.