chrM-1555-A-G

Variant names:

• chrM-1555-A-G
• rs267606617
• ENST00000389680.2:n.908A>G

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4 PP3 PS3_Moderate

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120590/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: RNR1 unassigned_transcript_4785 non_coding_transcript_exon
• Clinical Significance: Pathogenic; drug response reviewed by expert panel P:14 O:8 DEAF|-autism-spectrum-intellectual-disability|-possibly-antiatherosclerotic
• Conservation: PhyloP100: 3.25
• Publications: 55 publications found

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]

TRNV (HGNC:7500): (mitochondrially encoded tRNA valine)

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000389680.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-RNR1	ENST00000389680.2	TSL:6	n.908A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-TV	ENST00000387342.1	TSL:6	n.-47A>G		upstream_gene	N/A
	MT-RNR2	ENST00000387347.2	TSL:6	n.-116A>G		upstream_gene	N/A

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Gnomad homoplasmic AF: 0.0011 AC: 63 AN: 56401

Gnomad heteroplasmic AF: 0.00020 AC: 11 AN: 56401

Mitomap

Disease(s): DEAF|-autism-spectrum-intellectual-disability|-possibly-antiatherosclerotic

Status: Cfrm-[P]

ClinVar

ClinVar submissions

Significance: Pathogenic; drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Mitochondrial non-syndromic sensorineural hearing loss (3)
1	-	-	Aminoglycoside induced ototoxicity (1)
1	-	-	Aminoglycoside-induced deafness (2)
1	-	-	Aminoglycoside-induced deafness;C3151897:Mitochondrial non-syndromic sensorineural hearing loss (1)
1	-	-	Hearing loss, sensorineural, autosomal-mitochondrial type (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Rare genetic deafness (1)
1	-	-	Restrictive cardiomyopathy (1)
-	-	-	amikacin response - Toxicity (1)
-	-	-	aminoglycoside antibacterials response - Toxicity (1)
-	-	-	Gentamicin response (1)
-	-	-	gentamicin response - Toxicity (1)
-	-	-	kanamycin response - Toxicity (1)
-	-	-	streptomycin response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Hmtvar	Pathogenic	1.0
PhyloP100		3.3

Other links and lift over

dbSNP: rs267606617; hg19: chrM-1557;