rs121434475

Variant names:

• chrM-9997-T-A
• rs121434475
• unassigned_transcript_4807:c.7T>A

Your query was ambiguous. Multiple possible variants found:

• chrM-9997-T-A
• chrM-9997-T-C

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: TRNG missense
• Scores: Mitotip Pathogenic 20
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 Unspecified-patient-from-clinical-lab,MHCM
• Conservation: PhyloP100: 1.32

Genes affected

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

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]

COX3 (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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-9997-T-A is Pathogenic according to our data. Variant chrM-9997-T-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 690090.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNG	unassigned_transcript_4807	c.7T>A	p.Leu3Ile	missense_variant	Exon 1 of 1
ND3	unassigned_transcript_4808	c.-62T>A		upstream_gene_variant
COX3	unassigned_transcript_4806	c.*7T>A		downstream_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.

Mitomap

Unspecified-patient-from-clinical-lab,MHCM

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434475; hg19: chrM-9998;