rs121434471

Variant names:

• chrM-4291-T-C
• rs121434471
• unassigned_transcript_4790:c.29T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP1 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.4291T>C variant in MT-TI has been reported in five probands with primary mitochondrial disease (PMIDs: 15498972, 34607911; PS4_moderate). Affected individuals had variable hypomagnesemia and hypokalemia (consistent with Gitelman-like syndrome), migraines, sensorineural hearing loss, and hypertrophic cardiomyopathy. In one affected individual, ragged red fibers, increased subsarcolemmal staining, cytoplasmic lipid accumulation, increased glycogen, and dysmorphic cristae were seen on muscle biopsy (PMID:15498972). The variant was present at homoplasmy or near homoplasmy in all reported individuals. While the variant was also present at high levels in unaffected family members, no children of affected fathers had clinical features in one large pedigree (PMID:15498972, PP1). Fibroblasts from affected individuals showed decreased maximal mitochondrial respiration and reduced complex IV activity (PMID:34607911; PP4). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly benign (31.8 percentile) but HmtVAR predicts it to be deleterious with a score of 0.4. There are no cybrids or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. Of note, this is a highly compelling variant of uncertain significance given the consistent phenotype in affected individuals. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PP1, PP4, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120573/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNI unassigned_transcript_4790 missense
• Scores: Mitotip Uncertain 10
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:1 Hypomagnesemic-Metabolic-Syndrome-/-Gitelman-like-syndrome
• Conservation: PhyloP100: 5.91
• Publications: 2 publications found

Genes affected

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

MT-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]

MT-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]

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

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

TRNQ Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387365.1. 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-TI	ENST00000387365.1	TSL:6	n.29T>C		non_coding_transcript_exon	Exon 1 of 1
	MT-ND2	ENST00000361453.3	TSL:6	c.-179T>C		upstream_gene	N/A	ENSP00000355046.4	P03891
	MT-ND1	ENST00000361390.2	TSL:6	c.*29T>C		downstream_gene	N/A	ENSP00000354687.2	P03886

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Hypomagnesemic-Metabolic-Syndrome-/-Gitelman-like-syndrome

Status: Reported

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Hypomagnesemia, hypertension, and hypercholesterolemia, mitochondrial (3)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	10
Hmtvar	Pathogenic	0.40
PhyloP100		5.9

Other links and lift over

dbSNP: rs121434471; hg19: chrM-4292;