chrM-12258-C-A
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The ENST00000000000(TRNS2):c.52C>A(p.Leu18Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Consequence
ENST00000000000 missense
Scores
Clinical Significance
Conservation
Publications
- mitochondrial diseaseInheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
- MERRF syndromeInheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TRNS2 | unassigned_transcript_4813 | c.52C>A | p.Leu18Ile | missense_variant | Exon 1 of 1 | |||
ND5 | unassigned_transcript_4815 | c.-79C>A | upstream_gene_variant | |||||
TRNL2 | unassigned_transcript_4814 | c.-8C>A | upstream_gene_variant |
Ensembl
Frequencies
Mitomap
ClinVar
Submissions by phenotype
Mitochondrial disease Pathogenic:1
The m.12258C>A variant in MT-TS2 gene has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting). Family members of both probands were also affected. The age of onset was in adulthood and ranged from the 20s to 60s. Features seen in affected individuals include diabetes, cataracts, retinitis pigmentosa, hearing loss, and cerebellar ataxia (PMIDs: 9792552, 10090882). This variant segregated with disease in multiple affected members in both families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 10090882, 9792552). There are no reported de novo occurrences of this variant to our knowledge. There is one occurrence in population databases (one occurrence in Mitomap GenBank sequences, absent in gnomAD v3.1.2 and Helix dataset). Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (95.3 percentile) and HmtVAR predicts it to be pathogenic with a score of 0.4 (PP3). Single fiber studies support the functional impact of this variant (PS3_supporting) as the level of variant in COX-positive fibers ranged from 23-71%, while in COX-negative fibers was present at >85% heteroplasmy (PMID: 9792552). 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 March 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3, PS3_supporting. -
Retinitis pigmentosa-deafness syndrome Pathogenic:1
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Cerebellar ataxia, cataract, and diabetes mellitus Pathogenic:1
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Computational scores
Source: