rs118203893

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PS3_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254830/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNY unassigned_transcript_4798 synonymous
• Scores: Mitotip Benign 8.4
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 CPEO
• Conservation: PhyloP100: 1.50
• Publications: 0 publications found

Genes affected

TRNY (HGNC:7502): (mitochondrially encoded tRNA tyrosine)

MT-CO1 (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)

TRNC Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387409.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TY	ENST00000387409.1	TSL:6	n.15G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-CO1	ENST00000361624.2	TSL:6	c.-27C>T		upstream_gene	N/A	ENSP00000354499.2
	MT-TA	ENST00000387392.1	TSL:6	n.-222G>A		upstream_gene	N/A

Frequencies

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

Mitomap

Disease(s): CPEO

Status: Reported

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Kearns-Sayre syndrome (1)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	8.4
Hmtvar	Pathogenic	0.65
PhyloP100		1.5

Other links and lift over

dbSNP: rs118203893; hg19: chrM-5878;