chrM-4332-G-A

Variant names:

• chrM-4332-G-A
• rs199476141
• unassigned_transcript_4791:c.69C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.4332G>A variant in MT-TQ has been reported in one individual from one family to date (PMID:11171912), in a man with an atypical presentation of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). This individual had hearing loss beginning in his 20s and a stroke-like episode in his 40s. Muscle biopsy showed ragged red fibers and COX-deficient fibers, along with decreased activity of respiratory chain complex IV. The variant was present at 81% in muscle and undetectable in fibroblasts and skin. While the variant was absent in blood from his mother and brother, it was also undetectable in the proband’s blood, therefore it is unclear if this was a de novo variant. There are no large families reported in the medical literature to consider for evidence of segregation. Of note, there is another individual reported with MELAS and this variant, however insufficient clinical details were provided to include this case for consideration for this variant curation (PMID:20064630). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (81st percentile) as does HmtVar with a score of 0.7 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of heteroplasmy in COX-negative fibers (mean 99.3% and ranging from 98.8-99.7%, n=13) than in COX-positive fibers (mean 70.5% and ranging from 46.5-94.5%, n=11; p=0.002; PMID:11335700; PS3_supporting). 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 January 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254844/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNQ unassigned_transcript_4791 synonymous
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 O:1 Encephalopathy-/-MELAS
• Conservation: PhyloP100: 3.85
• Publications: 3 publications found

Genes affected

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

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]

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

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

TRNI Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy

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

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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: ENST00000387372.1. 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-TQ	ENST00000387372.1	TSL:6	n.69C>T		non_coding_transcript_exon	Exon 1 of 1
	MT-ND2	ENST00000361453.3	TSL:6	c.-138G>A		upstream_gene	N/A	ENSP00000355046.4	P03891
	MT-ND1	ENST00000361390.2	TSL:6	c.*70G>A		downstream_gene	N/A	ENSP00000354687.2	P03886

Frequencies

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

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56431

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56431

Mitomap

Disease(s): Encephalopathy-/-MELAS

Status: Cfrm-[VUS*]

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	MELAS syndrome (2)
-	1	-	Mitochondrial disease (1)
1	-	-	MT-TQ-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	0.70
PhyloP100		3.8

Other links and lift over

dbSNP: rs199476141; hg19: chrM-4333;