rs387906732

Variant names:

• chrM-5816-A-G
• rs387906732
• unassigned_transcript_4797:c.11T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The m.5816A>G variant in MT-TC has been reported in two unrelated families with primary mitochondrial disease (PS4_supporting; PMIDs: 17724295, 37771542). The first reported family had four affected individuals with variable clinical features including dystonia, seizures, tremor, fatigue, ptosis, pigmentary retinopathy, and optic atrophy. Muscle biopsies in these family members showed mosaic COX deficiency, normal respiratory chain enzyme activities, and decreased steady state levels of mt-tRNA Cys. The variant was homoplasmic in muscle and blood in these individuals (PMID:17724295). The second family reported had one affected individual, a girl, with dystonia, episodic vomiting, motor regression, tremor, and seizures. Skin fibroblast testing showed reduced basal resting oxygen consumption rate (OCR), ATP production, proton leak, maximal respiration, and reserve capacity OCR. The variant was present in blood and urine but heteroplasmy levels were not reported (PMID:37771542). The variant was present in additional family members of this second family however phenotypes and heteroplasmy levels were not reported. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor MitoTIP suggests this variant is pathogenic (59.9 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). 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 April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA128829/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNC unassigned_transcript_4797 missense
• Scores: Mitotip Uncertain 14
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 Progressive-Dystonia
• Conservation: PhyloP100: 7.03
• Publications: 1 publications found

Genes affected

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

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)

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

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 3 ACMG points.

• PS4: 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
TRNC	unassigned_transcript_4797	c.11T>C	p.Val4Ala	missense_variant	Exon 1 of 1
COX1	unassigned_transcript_4799	c.-88A>G		upstream_gene_variant
TRNN	unassigned_transcript_4796	c.-87T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO1	ENST00000361624.2	c.-88A>G		upstream_gene_variant		6		ENSP00000354499.2

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Progressive-Dystonia

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Dystonia, mitochondrial Pathogenic:1

Aug 28, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Apr 23, 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.5816A>G variant in MT-TC has been reported in two unrelated families with primary mitochondrial disease (PS4_supporting; PMIDs: 17724295, 37771542). The first reported family had four affected individuals with variable clinical features including dystonia, seizures, tremor, fatigue, ptosis, pigmentary retinopathy, and optic atrophy. Muscle biopsies in these family members showed mosaic COX deficiency, normal respiratory chain enzyme activities, and decreased steady state levels of mt-tRNA Cys. The variant was homoplasmic in muscle and blood in these individuals (PMID: 17724295). The second family reported had one affected individual, a girl, with dystonia, episodic vomiting, motor regression, tremor, and seizures. Skin fibroblast testing showed reduced basal resting oxygen consumption rate (OCR), ATP production, proton leak, maximal respiration, and reserve capacity OCR. The variant was present in blood and urine but heteroplasmy levels were not reported (PMID: 37771542). The variant was present in additional family members of this second family however phenotypes and heteroplasmy levels were not reported. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor MitoTIP suggests this variant is pathogenic (59.9 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). 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 April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	14
Hmtvar	Pathogenic	0.65
PhyloP100		7.0

Other links and lift over

dbSNP: rs387906732; hg19: chrM-5817;