rs118203892

Variant names:

• chrM-5884-AT-A
• rs118203892
• unassigned_transcript_4798:c.7delA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.5888delT variant in MT-TY has been reported in one individual with primary mitochondrial disease to date (PMID:11756614). This woman had bilateral ptosis, chronic progressive external ophthalmoplegia (CPEO), myopathy, and exercise intolerance onset in her 30s. Muscle biopsy showed ragged red fibers, COX-negative fibers, paracrystalline inclusions, and decreased activities of complexes I and IV. The variant was present at 78% in muscle and was undetectable in blood. The variant was also undetectable in blood from her mother, three siblings, and three children (although this cannot be considered a de novo occurrence as the variant was also undetectable in the proband’s blood; PMID 11756614). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (53.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (79.4%) than in COX positive fibers (19.8%), p<0.0001 (PS3_supporting, PMID:11756614). 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): PM2_supporting, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254829/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNY unassigned_transcript_4798 frameshift
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 1.52
• Publications: 1 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 3 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNY	unassigned_transcript_4798	c.7delA	p.Met3fs	frameshift_variant	Exon 1 of 1
COX1	unassigned_transcript_4799	c.-19delT		upstream_gene_variant
TRNN	unassigned_transcript_4796	c.-156delA		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO1	ENST00000361624.2	c.-19delT		upstream_gene_variant		6		ENSP00000354499.2

Frequencies

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

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Kearns-Sayre syndrome Pathogenic:1

Dec 26, 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.5888delT variant in MT-TY has been reported in one individual with primary mitochondrial disease to date (PMID: 11756614). This woman had bilateral ptosis, chronic progressive external ophthalmoplegia (CPEO), myopathy, and exercise intolerance onset in her 30s. Muscle biopsy showed ragged red fibers, COX-negative fibers, paracrystalline inclusions, and decreased activities of complexes I and IV. The variant was present at 78% in muscle and was undetectable in blood. The variant was also undetectable in blood from her mother, three siblings, and three children (although this cannot be considered a de novo occurrence as the variant was also undetectable in the proband’s blood; PMID 11756614). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (53.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (79.4%) than in COX positive fibers (19.8%), p<0.0001 (PS3_supporting, PMID: 11756614). 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): PM2_supporting, PP3, PS3_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
PhyloP100		1.5

Other links and lift over

dbSNP: rs118203892; hg19: chrM-5885;