rs267606619
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PM2PP5_Very_StrongBS2
The ENST00000389680.2(MT-RNR1):n.847C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic,drug response (★★★).
Frequency
Mitomap GenBank:
Absent
Consequence
MT-RNR1
ENST00000389680.2 non_coding_transcript_exon
ENST00000389680.2 non_coding_transcript_exon
Scores
Clinical Significance
DEAF
Conservation
PhyloP100: 1.28
Genes affected
MT-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
No frequency data in Mitomap. Probably very rare.
PP5
?
Variant M-1494-C-T is Pathogenic according to our data. Variant chrM-1494-C-T is described in ClinVar as [Likely_pathogenic, drug_response]. Clinvar id is 9632.Status of the report is reviewed_by_expert_panel, 3 stars.
BS2
?
High AC in GnomadMitoHomoplasmic at 13
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RNR1 | RNR1.1 use as main transcript | n.847C>T | non_coding_transcript_exon_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-RNR1 | ENST00000389680.2 | n.847C>T | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Gnomad homoplasmic
AF:
AC:
13
AN:
56433
Gnomad heteroplasmic
AF:
AC:
1
AN:
56433
Mitomap
DEAF
ClinVar
Significance: Likely pathogenic; drug response
Submissions summary: Pathogenic:5Other:8
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 10, 2006 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Aminoglycoside-induced deafness Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 10, 2006 | - - |
drug response, no assertion criteria provided | research | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 08, 2018 | - aminoglycoside antibacterials response - Toxicity/ADR |
Mitochondrial disease Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jul 11, 2022 | 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. - |
Aminoglycoside Ototoxicity Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 02, 2023 | 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. - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 24, 2023 | 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. - |
Gentamicin response Other:1
drug response, criteria provided, single submitter | curation | Medical Genetics Summaries | Aug 01, 2018 | Individuals who have the m.1494C > T variant are at risk of gentamicin-induced hearing loss. Adverse effect: Gentamicin-induced hearing loss |
gentamicin response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Jun 15, 2021 | 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. Drug-variant association: Toxicity |
aminoglycoside antibacterials response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Jun 15, 2021 | 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. Drug-variant association: Toxicity |
kanamycin response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Jun 15, 2021 | 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. Drug-variant association: Toxicity |
streptomycin response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Jun 15, 2021 | 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. Drug-variant association: Toxicity |
tobramycin response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Jun 15, 2021 | 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. Drug-variant association: Toxicity |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Hmtvar
Pathogenic
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at