rs121434476

Variant names:

• chrM-10010-T-C
• rs121434476
• unassigned_transcript_4807:c.20T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS4_Moderate PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120577/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNG unassigned_transcript_4807 missense
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 PEM
• Conservation: PhyloP100: 7.62
• Publications: 1 publications found

Genes affected

TRNG (HGNC:7486): (mitochondrially encoded tRNA glycine)

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]

MT-CO3 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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.
• 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: ENST00000387429.1. 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-TG	ENST00000387429.1	TSL:6	n.20T>C		non_coding_transcript_exon	Exon 1 of 1
	MT-ND3	ENST00000361227.2	TSL:6	c.-49T>C		upstream_gene	N/A	ENSP00000355206.2	P03897
	MT-CO3	ENST00000362079.2	TSL:6	c.*20T>C		downstream_gene	N/A	ENSP00000354982.2	P00414

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): PEM

Status: Cfrm-[VUS*]

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Exercise intolerance (1)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	0.55
PhyloP100		7.6

Other links and lift over

dbSNP: rs121434476; hg19: chrM-10011;