chrM-5545-C-T

Variant names:

• chrM-5545-C-T
• rs387906418
• unassigned_transcript_4794:c.34C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM6_Supporting PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.5545C>T variant in MT-TW has been reported in one individual with primary mitochondrial disease to date, in a boy with hypertrophic cardiomyopathy, hypotonia, lactic acidosis, developmental regression, seizures, slowly progressive chorea, proximal muscle weakness, ataxia, and dysmetria. Brain MRI showed diffuse brain atrophy and bilateral putaminal intensities. Muscle biopsy showed a diffuse reduction in COX activity with normal SDH staining. Respiratory chain enzyme activities in muscle showed reduced complex IV activity (12% of controls). The variant was present at 25% heteroplasmy in muscle, 13% in leukocytes, and 17% in skin fibroblasts (PMID:18337306). The variant was absent in leukocytes, urine, hair, and buccal sample from his mother (PMID:18337306; PM6_supporting). There are no other large families reported to consider evidence for segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (31±7%, n = 11) than in COX-positive fibers (3 ± 4%, n = 13), p<0.01 (PS3_supporting, PMID:18337306). Cybrid studies and translation assay further support the functional effect of this variant (PMID:18337306). The computational predictor MitoTIP suggests this variant is pathogenic (53 percentile) and HmtVAR predicts it to be pathogenic score of 0.7 (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 April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM6_supporting, PM2_supporting, PS3_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120543/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNW unassigned_transcript_4794 stop_gained
• Scores: Mitotip Uncertain 13
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 HCM-severe-multisystem-disorder
• Conservation: PhyloP100: 4.72
• Publications: 1 publications found

Genes affected

TRNW (HGNC:7501): (mitochondrially encoded tRNA tryptophan)

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]

TRNN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

TRNA (HGNC:7475): (mitochondrially encoded tRNA alanine)

TRNC (HGNC:7477): (mitochondrially encoded tRNA cysteine)

TRNC Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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: ENST00000387382.1. 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-TW	ENST00000387382.1	TSL:6	n.34C>T		non_coding_transcript_exon	Exon 1 of 1
	MT-ND2	ENST00000361453.3	TSL:6	c.*34C>T		downstream_gene	N/A	ENSP00000355046.4	P03891
	MT-TA	ENST00000387392.1	TSL:6	n.*42G>A		downstream_gene	N/A

Frequencies

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

Mitomap

Disease(s): HCM-severe-multisystem-disorder

Status: Reported

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Encephalocardiomyopathy, mitochondrial (1)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	13
Hmtvar	Pathogenic	0.70
PhyloP100		4.7

Other links and lift over

dbSNP: rs387906418; hg19: chrM-5546;