M-4409-T-C

Variant names:

• chrM-4409-T-C
• rs118203884
• unassigned_transcript_4792:c.8T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000000000(TRNM):​c.8T>C​(p.Val3Ala) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNM ENST00000000000 missense
• Scores: Mitotip Uncertain 12
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 Mitochondrial-myopathy
• Conservation: PhyloP100: 7.56
• Publications: 2 publications found

Genes affected

TRNM (HGNC:7492): (mitochondrially encoded tRNA methionine)

MT-ND2 (HGNC:7456): (mitochondrially encoded NADH dehydrogenase 2) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; multiple sclerosis; myocardial infarction; neurodegenerative disease (multiple); and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

TRNQ (HGNC:7495): (mitochondrially encoded tRNA glutamine)

TRNI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)

TRNI Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-4409-T-C is Pathogenic according to our data. Variant chrM-4409-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 9578.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387377.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TM	ENST00000387377.1	TSL:6	n.8T>C		non_coding_transcript_exon	Exon 1 of 1
	MT-ND2	ENST00000361453.3	TSL:6	c.-61T>C		upstream_gene	N/A	ENSP00000355046.4
	MT-ND1	ENST00000361390.2	TSL:6	c.*147T>C		downstream_gene	N/A	ENSP00000354687.2

Frequencies

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

Mitomap

Disease(s): Mitochondrial-myopathy

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Inborn mitochondrial myopathy Pathogenic:1

Dec 05, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mitochondrial disease Uncertain:1

May 28, 2024

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.4409T>C variant in MT-TM has been reported in one individual with primary mitochondrial disease (PMID: 9633749). This individual had severe exercise intolerance, muscle atrophy, muscle weakness, chronic progressive external ophthalmoplegia (CPEO), hearing impairment, and lactic acidosis. Leg muscle MRI showed fat infiltration and muscle atrophy. Muscle biopsy showed severe dystrophic features, ragged red fibers, COX-deficient fibers, SDH strongly positive staining, centrally nucleated fibers, fibrosis, and fat infiltration. Electron microscopy showed giant mitochondria with abnormal cristae structure and crystalloid inclusions. The variant was present at 8% in blood, 77% in muscle, and was undetectable in hair. The variant was undetectable in blood from the mother and three siblings (PMID: 9633749; PM6_supporting). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). MitoTIP predicts the variant is possible benign (46.5 percentile) and HmtVAR predicts the variant is pathogenic (score of 1). Single fiber testing showed higher levels of the variant in COX-negative fibers (69 ± 10%, n = 9) than in COX-positive fibers (39 ±9%, n = 10) p<0.04 (PMID: 9633749). Additional functional characterization showed disruption of the tRNA structure significantly reducing aminoacylation, failure form a stable tertiary complex with associated elongation factors preventing participation in chain elongation, and disrupted tRNA folding (PMID: 18835817; PS3_moderate). In summary, this variant meets criteria to be classified as uncertain significance 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 May 28, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PM6_supporting, PS3_moderate.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	12
Hmtvar	Pathogenic	1.0
PhyloP100		7.6

Other links and lift over

dbSNP: rs118203884; hg19: chrM-4410;