chrM-5877-C-T

Variant names:

• chrM-5877-C-T
• rs118203893
• unassigned_transcript_4798:c.15G>A

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:1 U:1 CPEO
• Conservation: PhyloP100: 1.50

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)

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
TRNY	unassigned_transcript_4798	c.15G>A	p.Glu5Glu	synonymous_variant	Exon 1 of 1
COX1	unassigned_transcript_4799	c.-27C>T		upstream_gene_variant
TRNN	unassigned_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:1 Uncertain:1

Revision: reviewed by expert panel

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

Other links and lift over

dbSNP: rs118203893; hg19: chrM-5878;