chrM-5728-T-C

Variant names:

• chrM-5728-T-C
• rs199476132
• unassigned_transcript_4796:c.2A>G
• TRNN p.Ter1Trpext*?

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM6 PS3_Supporting PP3 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The m.5728T>C variant in MT-TN has been reported in three unrelated individuals with primary mitochondrial disease (PS4_supporting). Onset was in infancy or childhood, and features seen in these individuals included myopathy, ataxia, developmental delay, multiorgan failure, ptosis, and ophthalmoplegia. The variant was seen at varying heteroplasmy levels in affected individuals, including undetectable to 50% in blood and 41-97% in muscle (PMIDs: 16908752, 23847141, 31026515). The variant was confirmed to have occurred de novo in one of the reported cases, as the variant was undetectable in the mother’s blood and muscle by next-generation sequencing (PMID:31026515, PM6). In another case, the variant appeared to have arisen de novo as it was not detected in blood from the healthy mother, two siblings, and maternal grandmother, however technology used at the time would not have detected low levels of the variant and additional tissues were not assessed (PMID:16908752). No details of family member testing were provided in the third case. There are no other large families reported in the medical literature with this variant to consider for evidence of segregation. There is one occurrence of this variant in GenBank dataset and it is absent in gnomAD v3.1.2 and in the Helix dataset, therefore the overall frequency is still very low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 71st percentile and HmtVAR also predicts it to be pathogenic, scoring 0.75 (PP3). Cybrid studies support the functional impact of this variant as a combined defect of complexes I and IV was seen (PS3_supporting; PMID:6908752). In summary, this variant meets criteria to be classified as likely pathogenic 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 February 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, PS3_supporting, PM2_supporting, PP3, PM6. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120585/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNN unassigned_transcript_4796 stop_lost
• Scores: Mitotip Uncertain 16
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 Multiorgan-failure-/-myopathy
• Conservation: PhyloP100: 1.98
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.2A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-CO1	ENST00000361624.2	TSL:6	c.-176T>C		upstream_gene	N/A	ENSP00000354499.2	P00395
	MT-ND2	ENST00000361453.3	TSL:6	c.*217T>C		downstream_gene	N/A	ENSP00000355046.4	P03891

Frequencies

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

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56428

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56428

Mitomap

Disease(s): Multiorgan-failure-/-myopathy

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (2)
1	-	-	MELAS syndrome (1)
1	-	-	MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 2 (1)
1	-	-	Mitochondrial disease (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	16
Hmtvar	Pathogenic	0.75
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs199476132;

hg19: chrM-5729;