rs267606617
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PP5_Very_StrongBS2
The ENST00000389680(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 non_coding_transcript_exon
ENST00000389680 non_coding_transcript_exon
Scores
Clinical Significance
DEAF; autism spectrum intellectual disability; possibly antiatherosclerotic
Conservation
PhyloP100: 3.25
Links
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
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 |
---|
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-RNR1 | ENST00000389680.2 | n.908A>G | non_coding_transcript_exon_variant | 1/1 | |||||
MT-TV | ENST00000387342.1 | upstream_gene_variant |
Frequencies
Gnomad homoplasmic
AF:
AC:
63
AN:
56401
Gnomad heteroplasmic
AF:
AC:
11
AN:
56401
Mitomap
DEAF; autism spectrum intellectual disability; possibly antiatherosclerotic
ClinVar
Significance: Pathogenic; drug response
Submissions summary: Pathogenic:8Other:8
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | GeneReviews | Jun 14, 2018 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 26, 2008 | - - |
Aminoglycoside-induced deafness Pathogenic:1Other:1
drug response, no assertion criteria provided | research | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Sep 25, 2018 | - aminoglycoside antibacterials response - Toxicity/ADR |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 26, 2008 | - - |
Restrictive cardiomyopathy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 26, 2008 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Aug 26, 2014 | - - |
Aminoglycoside-induced deafness;C3151897:Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1
Pathogenic, no assertion criteria provided | research | Donald Williams Parsons Laboratory, Baylor College of Medicine | Feb 27, 2014 | This 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. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 29, 2013 | The 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 - |
Mitochondrial disease Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Dec 15, 2022 | The 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. - |
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 |
Gentamicin response Other:1
drug response, criteria provided, single submitter | curation | Medical Genetics Summaries | Aug 01, 2018 | Individuals 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 |
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 |
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 |
amikacin 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