rs267606619

Variant names:

• chrM-1494-C-T
• rs267606619
• ENST00000389680.2:n.847C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4 PM5_Supporting PS3_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254847/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: RNR1 unassigned_transcript_4785 non_coding_transcript_exon
• Clinical Significance: Likely pathogenic; drug response reviewed by expert panel P:5 O:8 DEAF
• Conservation: PhyloP100: 1.28
• Publications: 28 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: Likely_pathogenic. The variant received 6 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.
• PM5: 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.847C>T		non_coding_transcript_exon	Exon 1 of 1
	MT-TV	ENST00000387342.1	TSL:6	n.-108C>T		upstream_gene	N/A
	MT-RNR2	ENST00000387347.2	TSL:6	n.-177C>T		upstream_gene	N/A

Frequencies

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

Gnomad homoplasmic AF: 0.00023 AC: 13 AN: 56433

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56433

Mitomap

Disease(s): DEAF

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic; drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Aminoglycoside Ototoxicity (1)
1	-	-	Aminoglycoside-induced deafness (2)
1	-	-	Mitochondrial disease (1)
1	-	-	Mitochondrial non-syndromic sensorineural hearing loss (2)
1	-	-	Rare genetic deafness (1)
-	-	-	aminoglycoside antibacterials response - Toxicity (1)
-	-	-	Gentamicin response (1)
-	-	-	gentamicin response - Toxicity (1)
-	-	-	kanamycin response - Toxicity (1)
-	-	-	streptomycin response - Toxicity (1)
-	-	-	tobramycin response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Hmtvar	Pathogenic	1.0
PhyloP100		1.3

Other links and lift over

dbSNP: rs267606619; hg19: chrM-1496;