rs121434476

chrM-10010-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000387429.1(MT-TG):n.20T>C variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TG ENST00000387429.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 PEM
• Conservation: PhyloP100: 7.62

Genes affected

MT-TG (HGNC:7486): (mitochondrially encoded tRNA glycine)

TRNG (HGNC:):

MT-ND3 (HGNC:7458): (mitochondrially encoded NADH dehydrogenase 3) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Mitotip and hmtvar scores support pathogenic criterium.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNG	TRNG.1	n.20T>C		non_coding_transcript_exon_variant	1/1
COX3	COX3.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TG	ENST00000387429.1	n.20T>C		non_coding_transcript_exon_variant	1/1
MT-ND3	ENST00000361227.2			upstream_gene_variant				P1
MT-CO3	ENST00000362079.2			downstream_gene_variant				P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

PEM

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Exercise intolerance Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 23, 2002

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Nov 14, 2022

The m.10010T>C variant in MT-TG has been reported in six unrelated individuals with primary mitochondrial disease. Features in affected individuals include Leigh syndrome (in two individuals), lactic acidosis, hyperCKemia, developmental delay, exercise intolerance, seizures, ataxia, sensorineural hearing loss, and optic atrophy. Muscle biopsies revealed ragged red fibers, COX-deficient fibers, and reduced activities of complexes I, III, and IV. The heteroplasmy levels of the variant in affected individuals ranged from 5.4% in blood to 92% in muscle. In cases that had more than one tissue tested, the heteroplasmy level was consistently and significantly higher in muscle (PS4_moderate; PMIDs: 26469001, 11971101, 16120360, 23847141, 9199564). There are no reported de novo occurrences of this variant to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing in two separate individuals showed higher levels of the variant in COX-negative fibers (97.3% and 91.7%) than in COX-positive fibers (87.2% and 58%) (PS3_supporting, PMIDs: 9199564, 11971101). The computational predictor MitoTIP suggests this variant is pathogenic (82.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). 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 November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PS3_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434476; hg19: chrM-10011;