rs199476141

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP5_Strong

Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNQ 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

Genes affected

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

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]

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

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]

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-4332-G-A is Pathogenic according to our data. Variant chrM-4332-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 9616.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNQ	unassigned_transcript_4791	c.69C>T	p.Ser23Ser	synonymous_variant	Exon 1 of 1
ND2	unassigned_transcript_4793	c.-138G>A		upstream_gene_variant
TRNM	unassigned_transcript_4792	c.-70G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56431

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56431

Mitomap

Encephalopathy-/-MELAS

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:1 Other:1

Feb 13, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

MT-TQ-related myopathy Pathogenic:1

Jul 30, 2024

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Uncertain:1

Jan 23, 2023

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.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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	0.70

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199476141; hg19: chrM-4333;