rs387906734

Variant names:

• chrM-586-G-A
• rs387906734
• unassigned_transcript_4784:c.10G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM6_Supporting PS3_Supporting PP3 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.586G>A variant in MT-TF has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting; PMIDs: 21060018, 31463198). One individual was a 57-year-old woman with hearing loss onset in her mid 40s that progressed to profound hearing loss in her 50s, myopathy and progressive exercise intolerance with reduced mobility and falls onset in her late 40s, and spasticity, facial grimacing, dementia, and psychiatric manifestations in her mid 50s (PMID:21060018). Brain imaging showed generalized cerebral, cerebellar, and brainstem atrophy. Cerebrospinal fluid lactate was elevated. Muscle biopsy showed ragged red fibers and COX-deficient fibers. The variant was present in muscle at 85% heteroplasmy, urinary epithelia at 29%, and blood at 3%. Her mother had died however DNA from paraffin-embedded breast tissue was obtained and revealed the variant at 13% heteroplasmy. The other individual was a 14-year-old boy with exercise intolerance and muscle weakness that followed a stable course (PMID:31463198). Brain imaging was normal. Lactate was elevated in blood. Muscle biopsy showed ragged red fibers, COX-negative fibers, and mitochondrial respiratory chain complexes I, III, and IV deficiency. The variant was present at >90% in muscle, 40% in urinary epithelia, and was present at trace levels in blood. The variant was undetectable in his mother’s blood and urinary epithelia (PM6_supporting; PMID:31463198). 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 (89.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.6 (PP3). Single fiber testing showed higher levels of the variant in COX-deficient fibers (99.4±0.2%, n=11) than in COX-positive fibers (72.1±8.5%, n=9; p<0.001; PS3_supporting, PMID:21060018). 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 10, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, PM6_supporting, PP3, PS3_supporting, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA128831/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNF unassigned_transcript_4784 missense
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 Extrapyramidal-disorder-with-akinesia-rigidity+-psychosis-and-SNHL
• Conservation: PhyloP100: 8.79
• Publications: 1 publications found

Genes affected

TRNF (HGNC:7481): (mitochondrially encoded tRNA phenylalanine)

MT-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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: ENST00000387314.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TF	ENST00000387314.1	TSL:6	n.10G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-RNR1	ENST00000389680.2	TSL:6	n.-62G>A		upstream_gene	N/A

Frequencies

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

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56431

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56431

Mitomap

Disease(s): Extrapyramidal-disorder-with-akinesia-rigidity+-psychosis-and-SNHL

Status: Reported

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	MELAS syndrome (1)
-	1	-	Mitochondrial disease (1)
1	-	-	Mitochondrial encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	18
Hmtvar	Pathogenic	0.60
PhyloP100		8.8

Other links and lift over

dbSNP: rs387906734; hg19: chrM-588;