rs786200951

Variant names:

• chrM-5610-G-A
• rs786200951
• unassigned_transcript_4795:c.46C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS3_Supporting PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.5610G>A variant in MT-TA has been reported in one individual with primary mitochondrial disease to date, in a 69-year-old woman with progressive limb girdle muscle weakness, dysarthria, and myopathic facies. Ragged red fibers and COX-negative fibers were noted on muscle biopsy. The variant was present at 91% heteroplasmy in muscle and 87% heteroplasmy in blood (PMID:25873012). The variant was present at lower (9-26% heteroplasmy) to undetectable levels in healthy family members although this expert panel notes some of these family members were not yet the age of the proband when she began to experience symptoms (PP1; PMID:25873012). There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (98%; n=20) than in COX-positive fibers (78%; n=21, P = 0.0002; PS3_supporting, PMID:25873012). Additionally, studies have shown decreased steady-state levels of tRNA Alanine in muscle from the proband (PMID:25873012). Computational predictors are discordant as MitoTIP suggests this variant is benign (38.7 percentile) and HmtVAR predicts it to be pathogenic (0.55). Of note, this variant is highly conserved among primates at 83%. 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 February 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP1, PM2_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274532/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNA unassigned_transcript_4795 stop_gained
• Scores: Mitotip Uncertain 11
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 Myopathy
• Conservation: PhyloP100: 1.26
• Publications: 1 publications found

Genes affected

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

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]

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

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 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.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNA	unassigned_transcript_4795	c.46C>T	p.Gln16*	stop_gained	Exon 1 of 1
ND2	unassigned_transcript_4793	c.*99G>A		downstream_gene_variant
TRNN	unassigned_transcript_4796	c.*47C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND2	ENST00000361453.3	c.*99G>A		downstream_gene_variant		6		ENSP00000355046.4

Frequencies

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

Mitomap

Disease(s): Myopathy

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Inborn mitochondrial myopathy Pathogenic:1

Dec 15, 2014

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mitochondrial disease Uncertain:1

Feb 12, 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.5610G>A variant in MT-TA has been reported in one individual with primary mitochondrial disease to date, in a 69-year-old woman with progressive limb girdle muscle weakness, dysarthria, and myopathic facies. Ragged red fibers and COX-negative fibers were noted on muscle biopsy. The variant was present at 91% heteroplasmy in muscle and 87% heteroplasmy in blood (PMID: 25873012). The variant was present at lower (9-26% heteroplasmy) to undetectable levels in healthy family members although this expert panel notes some of these family members were not yet the age of the proband when she began to experience symptoms (PP1; PMID: 25873012). There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (98%; n=20) than in COX-positive fibers (78%; n=21, P = 0.0002; PS3_supporting, PMID: 25873012). Additionally, studies have shown decreased steady-state levels of tRNA Alanine in muscle from the proband (PMID: 25873012). Computational predictors are discordant as MitoTIP suggests this variant is benign (38.7 percentile) and HmtVAR predicts it to be pathogenic (0.55). Of note, this variant is highly conserved among primates at 83%. 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 February 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PM2_supporting, PS3_supporting.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.55
PhyloP100		1.3

Other links and lift over

dbSNP: rs786200951; hg19: chrM-5611;