M-9997-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000000000(TRNG):​c.7T>A​(p.Leu3Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Mitomap GenBank:
Absent

Consequence

TRNG
ENST00000000000 missense

Scores

Mitotip
Pathogenic
20

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:1
Unspecified-patient-from-clinical-lab,MHCM

Conservation

PhyloP100: 1.32

Publications

1 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
No frequency data in Mitomap. Probably very rare.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRNGunassigned_transcript_4807 c.7T>A p.Leu3Met missense_variant Exon 1 of 1
ND3unassigned_transcript_4808 c.-62T>A upstream_gene_variant
COX3unassigned_transcript_4806 c.*7T>A downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MT-TGENST00000387429.1 linkn.7T>A non_coding_transcript_exon_variant Exon 1 of 1 6
MT-ND3ENST00000361227.2 linkc.-62T>A upstream_gene_variant 6 ENSP00000355206.2 P03897
MT-CO3ENST00000362079.2 linkc.*7T>A downstream_gene_variant 6 ENSP00000354982.2 P00414

Frequencies

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

Mitomap

Disease(s): Unspecified-patient-from-clinical-lab,MHCM
Status: Reported,Reported
Publication(s): 31965079, 8079988

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

MELAS syndrome Pathogenic:1
Jul 12, 2019
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The NC_012920.1:m.9997T>A variant in MT-TG gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PM5, PM7, PM9, PM10 -

Mitochondrial disease Uncertain:1
Jul 22, 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.9997T>A variant in MT-TG has been reported in one individual to date, however clinical details were not provided (PMID: 31965079). Similarly, there is no available information on segregation in family members or de novo status. It is possible this individual was reported in a poster abstract submitted by Roggenbuck et al., 2016 (https://www.neurology.org/doi/10.1212/WNL.86.16_supplement.P5.016), but this has not been confirmed. The individual reported with this variant in this abstract was a man with exercise intolerance, myalgia, muscle weakness, ptosis, neuropathy, dilated cardiomyopathy, and renal disease. Respiratory chain enzyme testing on muscle showed low cytochrome c oxidase activity but exact values were not provided. The variant was reported to be present at homoplasmy in the proband and was also reported in other maternal family members with varying clinical features, however details were not provided. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor MitoTIP suggests this variant is deleterious (95.2 percentile) and HmtVAR predicts it to be deleterious with a score of 0.35 (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 July 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
Mitotip
Pathogenic
20
Hmtvar
Benign
0.050
PhyloP100
1.3

Publications

Other links and lift over

dbSNP: rs121434475; hg19: chrM-9998; API