rs387906418

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNW 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

Genes affected

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

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)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNW	unassigned_transcript_4794	c.34C>T	p.Gln12*	stop_gained	Exon 1 of 1
ND2	unassigned_transcript_4793	c.*34C>T		downstream_gene_variant
TRNN	unassigned_transcript_4796	c.*112G>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

HCM-severe-multisystem-disorder

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Encephalocardiomyopathy, mitochondrial Pathogenic:1

Jun 15, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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.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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	13
Hmtvar	Pathogenic	0.70

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906418; hg19: chrM-5546;