rs267606617

chrM-1555-A-G

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.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
• Clinical Significance: Pathogenic; drug response reviewed by expert panel P:11 O:8 DEAF|-autism-spectrum-intellectual-disability|-possibly-antiatherosclerotic
• Conservation: PhyloP100: 3.25

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:):

MT-TV (HGNC:7500): (mitochondrially encoded tRNA valine)

ACMG classification

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
RNR1	RNR1.1	n.908A>G		non_coding_transcript_exon_variant	1/1
TRNV	TRNV.1			upstream_gene_variant

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

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:11 Other:8

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	GeneReviews	Jun 14, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 26, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 13, 2023	The 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. -

Aminoglycoside-induced deafness Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 26, 2008	- -
drug response, no assertion criteria provided	research	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Sep 25, 2018	- aminoglycoside antibacterials response - Toxicity/ADR

Aminoglycoside induced ototoxicity Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 26, 2023

The m.1555A>G variant is an established pathogenic variant that has previously been reported in individuals with aminoglycoside-induced hearing loss [PMID:20301595] , and it has been deposited in ClinVar [ClinVar ID= 9628]. The m.1555A>G variant has been found to be enriched in individuals with aminoglycoside induced hearing loss and compared to nonsyndromic hearing loss [PMID: 17698299]. In vitro studies demonstrated specific binding of aminoglycosides to the m.1555A>G variant in a 12S rRNA construct [PMID: 20301595]. Based on available evidence this inherited homoplasmic mitochondrial m.1555A>G variant is classified as Pathogenic. -

Restrictive cardiomyopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 26, 2008

- -

Hearing loss, sensorineural, autosomal-mitochondrial type Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Oct 24, 2023

The 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 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. -

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. -

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 -

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

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

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: 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: rs267606617; hg19: chrM-1557;