rs121434458
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP1_ModeratePS3_SupportingPP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The m.5591G>A variant in MT-TA has been reported in one individual with primary mitochondrial disease (PMIDs: 16476954, 29139113). This was a male who presented in his 40s with progressive muscle weakness, myalgia, elevated creatine kinase (CK), and lactate. Muscle biopsy noted COX deficient fibers, increased subsarcolemmal mitochondrial accumulation, and electron transport chain complexes I, III, and IV deficiency. Heteroplasmy ranged from 79% (blood) to >99% (hair shaft). This variant segregated with disease manifestations in this family as an unaffected younger brother had the variant present at 67% heteroplasmy in urine and an unaffected older brother had undetectable levels of the variant in urine (PP1_moderate; PMID:16476954). 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). The computational predictor MitoTIP suggests this variant is pathogenic (68.6 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (99.5%) than in COX-positive fibers (72.3%), p 0.0001 (PS3_supporting, PMID:16476954). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt likely pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP1_moderate, PS3_supporting, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254845/MONDO:0044970/015
Frequency
Consequence
unassigned_transcript_4795 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: ENST00000387392.1. 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-TA | ENST00000387392.1 | TSL:6 | n.65C>T | non_coding_transcript_exon | Exon 1 of 1 | ||||
| MT-ND2 | ENST00000361453.3 | TSL:6 | c.*80G>A | downstream_gene | N/A | ENSP00000355046.4 | |||
| MT-TW | ENST00000387382.1 | TSL:6 | n.*12G>A | downstream_gene | N/A |
Frequencies
Mitomap
ClinVar
Submissions by phenotype
Mitochondrial disease Pathogenic:1Uncertain:1
The m.5591G>A variant in MT-TA has been reported in one individual with primary mitochondrial disease (PMIDs: 16476954, 29139113). This was a male who presented in his 40s with progressive muscle weakness, myalgia, elevated creatine kinase (CK), and lactate. Muscle biopsy noted COX deficient fibers, increased subsarcolemmal mitochondrial accumulation, and electron transport chain complexes I, III, and IV deficiency. Heteroplasmy ranged from 79% (blood) to >99% (hair shaft). This variant segregated with disease manifestations in this family as an unaffected younger brother had the variant present at 67% heteroplasmy in urine and an unaffected older brother had undetectable levels of the variant in urine (PP1_moderate; PMID: 16476954). 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). The computational predictor MitoTIP suggests this variant is pathogenic (68.6 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (99.5%) than in COX-positive fibers (72.3%), p 0.0001 (PS3_supporting, PMID: 16476954). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt likely pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PS3_supporting, PP3, PM2_supporting.
MELAS syndrome Pathogenic:1
The NC_012920.1:m.5591G>A variant in MT-TA gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PM8, PM9, PP3, PP6
Inborn mitochondrial myopathy Pathogenic:1
not provided Other:1
Variant classified as Likely pathogenic and reported on 08-26-2022 by GeneDx. Participant is 6% heteroplasmic for variant. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Computational scores
Source: