ClinVar Genomic variation as it relates to human health

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

The m.1494C>T variant in the MT-RNR1 gene 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 (PS4; PMIDs: 34467602, 20100600, 17084680, 16380089, 17434445, 17698299, 17698030, 30693673, 14681830). Given the homoplasmic nature of this variant, familial segregation cannot be applied for PP1. There are no reports of de novo occurrences to our knowledge. This variant occurs in a highly conserved area and forms U1494-1555A base pair which is in the same position of the C1494-1555G pair created in a well-known pathogenic variant m.1555A>G (PM5_supporting; PMID: 14681830). Cybrid studies support the functional impact of this variant. Compared to control cybrids, there was a decrease in mitochondrial protein synthesis and high concentration of paromomycin in cybrids derived from three symptomatic and two asymptomatic individuals carrying the m.1494C>T variant (PS3_supporting; PMID: 15722487). This variant is present in population databases (Mitomap's 51,863 sequences: AF=0.007%; Helix's 196,554 sequences: AF=0.021%; and gnomAD v3.1.2: AF=0.0023% as this is homoplasmic in 13 individuals and heteroplasmic in one individual). Given the frequency of this variant, it does not meet PM2 criterion. There is limited computational scoring for rRNA variants precluding PP3 criterion. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM5_supporting.

Individuals who have the m.1494C > T variant are at risk of gentamicin-induced hearing loss.

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.

The m.1494C>T mitochondrial variant (98% heteroplasmy) has been reported in homoplasmic or at high heteroplasmy levels in many affected individuals in the literature [PMID:20301595, 16380089, 14681830]. The mitochondrial 1494 position is in a highly conserved region of the mitochondrial genome and forms a U1494-1555A base pair, and the m.1555 nucleotide is also a well known mitochondrial variant associated with aminoglycoside ototoxicity [PMID:20301595]. Functional studies have demonstrated that the m.1494C>T variant leads to decreased mitochondrial protein synthesis and respiratory capacity [PMID:15722487]. The m.1494C>T variant is reported as Likely Pathogenic in ClinVar by the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel (VarID:9632), and has been curated with Level 1A evidence for ototoxicity for several drugs including aminoglycoside antibacterials by PharmGKB (https://www.pharmgkb.org/haplotype/PA166229254/clinicalAnnotation). Given the available evidence, the m.1494C>T mitochondrial variant is reported as Likely Pathogenic.