M-4300-A-G

Variant names:

• chrM-4300-A-G
• rs121434470
• unassigned_transcript_4790:c.38A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PP1_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.4300A>G variant in MT-TI has been reported in at least 17 individuals from eight families with hypertrophic cardiomyopathy. Affected individuals had variable ages of onset (11 months old to 40s). All cases developed hypertrophic cardiomyopathy. Muscle biopsy revealed COX negative fibers in cardiac tissue and one case had ragged red fibers in skeletal muscle. Heteroplasmy levels were predominantly the same in all affected probands as the variant was present at homoplasmy or > 97% in all tissues. Other affected family members did harbor the variant at 60-100%. Of note, some healthy family members had the variant ranging from 40-100% (PS4_moderate; PMIDs: 10065021, 7646516, 12767666, 12711217, 23847141). This variant segregated with disease in a family with LVH with diffuse hypertrophy as the proband's heteroplasmy was 98% in heart, 85% in muscle, and 95% in blood. His seven affected maternal relatives had heteroplasmy levels ranging from 60-92% in blood. His 12 unaffected relatives available for testing heteroplasmy ranged 50-78% in blood (PP1_moderate, PMID:1006502). There are no reported de novo occurrences of this variant to our knowledge. There are three occurrences of this variant in Helix dataset (frequency of 0.001%) that includes two homoplasmic and one heteroplasmic individuals. This variant is absent in gnomAD v3.1.2 and in GenBank dataset therefore the frequency is still low enough to meet criteria for 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 pathogenic (79.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic 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 September 12, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM2_supporting, PP3, PP1_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254842/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNI unassigned_transcript_4790 stop_lost
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 MICM
• Conservation: PhyloP100: 1.74
• Publications: 6 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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: 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.38A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-ND2	ENST00000361453.3	TSL:6	c.-170A>G		upstream_gene	N/A	ENSP00000355046.4	P03891
	MT-ND1	ENST00000361390.2	TSL:6	c.*38A>G		downstream_gene	N/A	ENSP00000354687.2	P03886

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MICM

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	MERRF syndrome (1)
1	-	-	Mitochondrial disease (1)
1	-	-	MT-TI-related disorder (1)
1	-	-	Primary dilated cardiomyopathy;C0205700:Asymmetric septal hypertrophy (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	0.75
PhyloP100		1.7
Mutation Taster		=95/5	polymorphism

Other links and lift over

dbSNP: rs121434470; hg19: chrM-4301;