rs199476132
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Consequence
stop_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNN | unassigned_transcript_4796 | c.2A>G | p.Ter1Trpext*? | stop_lost | Exon 1 of 1 | |||
| COX1 | unassigned_transcript_4799 | c.-176T>C | upstream_gene_variant | |||||
| TRNA | unassigned_transcript_4795 | c.-73A>G | upstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:2
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Mitochondrial disease Pathogenic:1
The m.5728T>C variant in MT-TN has been reported in three unrelated individuals with primary mitochondrial disease (PS4_supporting). Onset was in infancy or childhood, and features seen in these individuals included myopathy, ataxia, developmental delay, multiorgan failure, ptosis, and ophthalmoplegia. The variant was seen at varying heteroplasmy levels in affected individuals, including undetectable to 50% in blood and 41-97% in muscle (PMIDs: 16908752, 23847141, 31026515). The variant was confirmed to have occurred de novo in one of the reported cases, as the variant was undetectable in the mother’s blood and muscle by next-generation sequencing (PMID: 31026515, PM6). In another case, the variant appeared to have arisen de novo as it was not detected in blood from the healthy mother, two siblings, and maternal grandmother, however technology used at the time would not have detected low levels of the variant and additional tissues were not assessed (PMID: 16908752). No details of family member testing were provided in the third case. There are no other large families reported in the medical literature with this variant to consider for evidence of segregation. There is one occurrence of this variant in GenBank dataset and it is absent in gnomAD v3.1.2 and in the Helix dataset, therefore the overall frequency is still very low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 71st percentile and HmtVAR also predicts it to be pathogenic, scoring 0.75 (PP3). Cybrid studies support the functional impact of this variant as a combined defect of complexes I and IV was seen (PS3_supporting; PMID: 6908752). 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 February 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PS3_supporting, PM2_supporting, PP3, PM6. -
MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 2 Pathogenic:1
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MELAS syndrome Pathogenic:1
The NC_012920.1:m.5728T>C variant in MT-TN 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 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at