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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNI	unassigned_transcript_4790	c.29T>C	p.Leu10Ser	missense_variant	Exon 1 of 1
ND2	unassigned_transcript_4793	c.-179T>C		upstream_gene_variant
TRNM	unassigned_transcript_4792	c.-111T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND2	ENST00000361453.3	c.-179T>C		upstream_gene_variant		6		ENSP00000355046.4
MT-ND1	ENST00000361390.2	c.*29T>C		downstream_gene_variant		6		ENSP00000354687.2

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

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypomagnesemia, hypertension, and hypercholesterolemia, mitochondrial Pathogenic:3

Nov 09, 2022

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 12, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 07, 2021

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The m.4291T>C variant was observed in 4 families affected by hypomagnesemia with renal magnesium wasting and hypokalemia.(Viering et al. 2021) The (near) homoplasmic variant cosegregated with disease. The variant was scored as pathogenic when using the system published by Wong et al. (2020) as basis: PS2, PS4, PM9, PM10, PP6 (additionally, PP7 and PS5 were previously met in a study by Wilson et al. 2004). -

Mitochondrial disease Uncertain:1

Apr 23, 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.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. -

Computational scores

Source: dbNSFP v4.3

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;