chrM-5877-C-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

TRNY
synonymous

Scores

Mitotip
Benign
8.4

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:1
CPEO

Conservation

PhyloP100: 1.50
Variant links:
Genes affected
TRNY (HGNC:7502): (mitochondrially encoded tRNA tyrosine)
COX1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [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)

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ACMG classification

Classification made for transcript

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
TRNYunassigned_transcript_4798 c.15G>A p.Glu5Glu synonymous_variant Exon 1 of 1
COX1unassigned_transcript_4799 c.-27C>T upstream_gene_variant
TRNNunassigned_transcript_4796 c.-148G>A upstream_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

CPEO

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Kearns-Sayre syndrome Pathogenic:1
Oct 01, 2001
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Mitochondrial disease Uncertain:1
Jun 24, 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.5877C>T variant in MT-TY has been reported in one individual with primary mitochondrial disease (PMID: 11594340). This individual had proximal muscle weakness, ptosis, and external ophthalmoplegia onset at age 28 years. She also had episodic diarrhea and atrioventricular block. Muscle biopsy showed ragged red fibers and COX-negative fibers. The variant was present at 73% heteroplasmy in muscle and 0.7% in blood. The variant was present in blood from her mother who had ptosis (heteroplasmy not reported) and in her two healthy children, although they were younger than the proband at the age of symptom onset. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictors are discordant as MitoTIP suggests this variant is benign (24.8 percentile) and HmtVAR predicts it to be pathogenic (0.65). Cybrid studies support the functional impact of this variant as decreased viability and oxygen consumption were associated with higher heteroplasmy levels (PS3_supporting; PMID: 11594340). 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 June 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
Mitotip
Benign
8.4
Hmtvar
Pathogenic
0.65

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs118203893; hg19: chrM-5878; API