rs267606619

chrM-1494-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PM2 PP5_Very_Strong BS2

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
• Clinical Significance: Likely pathogenic; drug response reviewed by expert panel P:5 O:8 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]

RNR1 (HGNC:):

ACMG classification

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	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

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Gnomad homoplasmic AF: 0.00023 AC: 13 AN: 56433

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56433

Mitomap

DEAF

ClinVar

Significance: Likely pathogenic; drug response

Submissions summary: Pathogenic:5 Other:8

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 10, 2006	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Aminoglycoside-induced deafness Pathogenic:1 Other:1

drug response, no assertion criteria provided	research	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 08, 2018	- aminoglycoside antibacterials response - Toxicity/ADR
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 10, 2006	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Hmtvar	Pathogenic	1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606619; hg19: chrM-1496;