rs1603220093

Variant names:

• chrM-5702-A-G
• rs1603220093
• unassigned_transcript_4796:c.28T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM6_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.5702A>G variant in MT-TN has been reported in one individual with primary mitochondrial disease to date (PMID:32161153; this appears to be the same individual reported in an abstract, https://www.nmd-journal.com/article/S0960-8966(16)30622-8/abstract, and included in the ClinVar submission for this variant). Clinical features in this woman include ophthalmoplegia, ptosis, myopathy, and ragged red and COX-negative fibers on muscle biopsy. The variant is present in the proband at 60% heteroplasmy muscle, 10% in urine, and absent in blood and skin fibroblasts. The variant is absent in blood and urine from her mother and four asymptomatic siblings (PM6_supporting; https://www.nmd-journal.com/article/S0960-8966(16)30622-8/abstract). There are no additional individuals or families reported with de novo occurrences of this variant or with this variant segregating with clinical manifestations to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 73.9%; HmtVAR: 0.05). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 September 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM6_supporting, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA913180290/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNN unassigned_transcript_4796 synonymous
• Scores: Mitotip Uncertain 16
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 4.79
• Publications: 0 publications found

Genes affected

TRNN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

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]

MT-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]

TRNA (HGNC:7475): (mitochondrially encoded tRNA alanine)

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

TRNC (HGNC:7477): (mitochondrially encoded tRNA cysteine)

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

TRNY Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387400.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TN	ENST00000387400.1	TSL:6	n.28T>C		non_coding_transcript_exon	Exon 1 of 1
	MT-CO1	ENST00000361624.2	TSL:6	c.-202A>G		upstream_gene	N/A	ENSP00000354499.2	P00395
	MT-ND2	ENST00000361453.3	TSL:6	c.*191A>G		downstream_gene	N/A	ENSP00000355046.4	P03891

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

No disease associated.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial disease (1)
1	-	-	Ptosis;C0162292:External ophthalmoplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	16
Hmtvar	Benign	0.050
PhyloP100		4.8

Other links and lift over

dbSNP: rs1603220093; hg19: chrM-5703;