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rs267606617

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PM2PP5_Very_StrongBS2

The ENST00000389680.2(MT-RNR1):n.908A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic,drug response (★★★).

Frequency

Mitomap GenBank:
Absent

Consequence

MT-RNR1
ENST00000389680.2 non_coding_transcript_exon

Scores

Clinical Significance

Pathogenic; drug response reviewed by expert panel P:10O:8
DEAF|-autism-spectrum-intellectual-disability|-possibly-antiatherosclerotic

Conservation

PhyloP100: 3.25
Variant links:
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]
MT-TV (HGNC:7500): (mitochondrially encoded tRNA valine)

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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-1555-A-G is Pathogenic according to our data. Variant chrM-1555-A-G is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 9628.Status of the report is reviewed_by_expert_panel, 3 stars.
BS2
High AC in GnomadMitoHomoplasmic at 63

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RNR1RNR1.1 use as main transcriptn.908A>G non_coding_transcript_exon_variant 1/1
TRNVTRNV.1 use as main transcript upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MT-RNR1ENST00000389680.2 linkuse as main transcriptn.908A>G non_coding_transcript_exon_variant 1/1
MT-TVENST00000387342.1 linkuse as main transcript upstream_gene_variant

Frequencies

GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Gnomad homoplasmic
AF:
0.0011
AC:
63
AN:
56401
Gnomad heteroplasmic
AF:
0.00020
AC:
11
AN:
56401

Mitomap

DEAF|-autism-spectrum-intellectual-disability|-possibly-antiatherosclerotic

ClinVar

Significance: Pathogenic; drug response
Submissions summary: Pathogenic:10Other:8
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:3
Pathogenic, no assertion criteria providedliterature onlyGeneReviewsJun 14, 2018- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaSep 13, 2023The MT-RNR1 m.1555A>G mitochondrial variant is widely reported in the literature in individuals with mitochondrial nonsyndromic hearing loss and deafness. Across a selection of the literature, the variant has been reported in at least 16 individuals with hearing loss (PMID: 7689389; 8285309; 9040738; 8800928; 9490575; 12920080; 20301595). 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. Whilst this variant is present in a homoplasmic state in most affected individuals, the level of heteroplasmy of this variant shows a significant correlation with the clinical signs the severity and onset of disease in at least seven unrelated families (PMID: 12920080; 22475488). Cybrid studies consistently demonstrate that the m.1555A>G variant reduces mitochondrial translation and cell growth (PMID: 8687424; 11230176). Additional functional studies in patient cells and single fiber testing support the functional impact of this variant (PMID: 8817331; 9915970) Multiple lines of computational evidence including MitoTIP and HmtVar suggest this variant may have a deleterious effect on the function of this rRNA. Based on the available evidence, the m.1555A>G variant is classified as pathogenic for mitochondrial nonsyndromic hearing loss and deafness. -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 26, 2008- -
Aminoglycoside-induced deafness Pathogenic:1Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 26, 2008- -
drug response, no assertion criteria providedresearchEquipe Genetique des Anomalies du Developpement, Université de BourgogneSep 25, 2018- aminoglycoside antibacterials response - Toxicity/ADR
Restrictive cardiomyopathy Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 26, 2008- -
Hearing loss, sensorineural, autosomal-mitochondrial type Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingDiagnostics Centre, Carl Von Ossietzky University OldenburgOct 24, 2023The variant MT-RNR1:n.908A>G, m.1555A>G is located in the 12S rRNA gene (MT-RNR1) and results from an adenine to guanine at nucleotide position 1555. It has been described in numerous cases with mitochondrial non-syndromic hearing loss (PMID: 7689389, 1613771, 8285309, 8414970, 9111378, 9040738, 9490575, 9831149, 10661905, 12031626, 12920080, 16935512, 20123042, 22317974, 23357420, 24252789, 11870684). Although the variant is present at homoplasmy in unaffected individuals, multiple individuals harboring the variant were reported to have hearing loss after amynoglycoside exposure. Non amynoglycoside exposure-related loss hering have been also reported. Age of onset of hearing loss ranged from infancy (after aminoglycoside exposure) to adulthood. Overall, aminoglycoside-based antibiotic treatments are known to increase the risk of hearing loss in carriers of this alteration (PMID: 29805548, 25515069). Multiple studies provide experimental evidences supporting a deleterious functional effect of the variant (PMID: 11230176, 8817331, 8687424). The variant is not considered rare in the overall population (MAF 0.1% for homoplasmy in gnomAD V3.1). The ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel suggest to classify of Pathogenic (Clinvar: 9628). Based on available evidence, the variant is classified as Likely Pathogenic. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsAug 26, 2014- -
Aminoglycoside-induced deafness;C3151897:Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1
Pathogenic, no assertion criteria providedresearchDonald Williams Parsons Laboratory, Baylor College of MedicineFeb 27, 2014This variant has been previously reported as disease-causing. It was an incidental finding in our study, in a 4-month-old female with kaposiform hemangioendothelioma. There was 65% heteroplasmy, and it was not detected in the mother, although heteroplasmy below 20% may not be detectable. -
Mitochondrial disease Pathogenic:1
Pathogenic, reviewed by expert panelcurationClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGenDec 15, 2022The m.1555A>G variant in MT-RNR1 has been reported in more than 65 individuals with primary mitochondrial disease, and the only consistent reported feature in affected individuals was hearing loss (PS4; 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 concerns. These concerns 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). There are no de novo occurrences of this variant reported to our knowledge. Many extended families have been reported in the medical literature however the variant was present at homoplasmy in both affected and unaffected family members, thus preventing consideration for PP1. The computational predictor HmtVAR predicts it to be pathogenic score of 1 (PP3). This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. Several studies in patient cells (PMIDs: 8817331, 9915970), cybrids (PMIDs: 8687424, 11230176), and single fiber testing (PMID: 9915970) support the functional impact of this variant (PS3_moderate). This variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature and/or have reduced penetrance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 15, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP3, PS3_supporting. -
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 29, 2013The m.1555A>G variant in MTRNR1 has been reported in many individuals with heari ng loss (often after exposure to aminoglycosides) and segregated in many affecte d matrilineal relatives (Prezant 1993, Pandya 1997, Usami 1997). The variant ha s been identified in 0.6-12% of hearing impaired individuals (Chen 2011, Yelvert on 2013), in contrast to 0.1-0.3% of the general population (Bitner-Glindzicz 20 09, Rahman 2012, Wang 2011, Wu 2011). Individuals with this variant usually pass newborn hearing screen, but develop aminoglycoside-induced or late-onset progre ssive hearing loss (Usami 2000, Lu 2009, Lu 2010). The penetrance is incomplete, but higher with aminoglycoside exposure than without, and the clinical manifest ation is influenced by the degree of heteroplasmy, environmental factors, haplog roup background, and other genetic modifiers (Lu 2010). This variant is in a reg ion of the 12S rRNA gene in which aminoglycosides are known to bind, and in whic h aminoglycoside resistance mutations have been described in other species. Alt hough this variant is present in other primate species, it has been shown that c ells with this variant are susceptible to aminoglycosides (Pacheu-Grau 2011). I n summary, this variant meets criteria to be classified as pathogenic based upon the over-representation of the variant in individuals with aminoglycoside-induc ed hearing loss, segregation in affected matrilineal relatives, and functional s tudies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Supporting -
Gentamicin response Other:1
drug response, criteria provided, single submittercurationMedical Genetics SummariesAug 01, 2018Individuals who have the m.1555A>G variant are at risk of gentamicin-induced hearing loss. A single, therapeutic, dose of gentamicin may result in moderate to profound hearing loss that is bilateral and irreversible. Adverse effect: Gentamicin-induced hearing loss
gentamicin response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBJun 15, 2021PharmGKB 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 panelcurationPharmGKBJun 15, 2021PharmGKB 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 panelcurationPharmGKBJun 15, 2021PharmGKB 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 panelcurationPharmGKBJun 15, 2021PharmGKB 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
amikacin response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBJun 15, 2021PharmGKB 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 panelcurationPharmGKBJun 15, 2021PharmGKB 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267606617; hg19: chrM-1557; API