Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document
  • There was no gene found in the curated document received from the VCI/VCEP
  • Gene listed was thus derived from ClinVar and/or CAR
  • The variant label for this record ("m.5728T>C") does not appear to be in HGVS format

Variant: m.5728T>C

CA120585

9622 (ClinVar)

Gene: MT-TN
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
Link to MONDO
UUID: d626e633-772b-4527-b217-37b5b5c9689a

HGVS expressions

NC_012920.1:m.5728T>C
J01415.2:m.5728T>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 5
PP3 PM6 PS4_Supporting PS3_Supporting PM2_Supporting
Not Met criteria codes 1
PP1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
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.
Met criteria codes
PP3
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).
PM6
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.
PS4_Supporting
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).
PS3_Supporting
Transmitochondrial cybrids carrying more than 55% mutant mitochondrial DNA showed deficiencies of complexes I and IV, matching the biochemical profile found using spectrophotometric analysis and blue native PAGE activity staining of muscle tissue and cultured fibroblasts. [PMID16908752]
Transmitochondrial cybrids carrying more than 55% mutant mitochondrial DNA showed deficiencies of complexes I and IV, matching the biochemical profile found using spectrophotometric analysis and blue native PAGE activity staining of muscle tissue and cultured fibroblasts. [PMID16908752] PubMed:16908752
PM2_Supporting
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).
Not Met criteria codes
PP1
There are no other large families reported in the medical literature with this variant to consider for evidence of segregation.
Approved on: 2023-02-13
Published on: 2023-03-30
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