The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • There was no gene found in the curated document received from the VCI/VCEP
  • The variant label for this record ("m.15923A>G") does not appear to be in HGVS format
  • No CSPEC computer assertion could be determined for this classification!


Variant: m.15923A>G

CA130372

39575 (ClinVar)

Gene: N/A
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
UUID: a6d8d41e-e48a-43f1-ab47-dbb15480f0da
Approved on: 2023-06-26
Published on: 2024-07-24

HGVS expressions

NC_012920.1:m.15923A>G
J01415.2:m.15923A>G

Likely Pathogenic

Met criteria codes 3
PS3_Moderate PS4_Moderate PM2_Supporting
Not Met criteria codes 5
PP1 PP3 PM6 BP4 PS2

Evidence Links 0

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.15923A>G variant in MT-TT has been reported in four individuals with primary mitochondrial disease from four unrelated families (PS4_moderate; PMIDs: 1645537, 22638997, 29760464, 30236074). Age of onset varied from the second day of life to the 50s. Affected individuals had features consistent with neonatal lactic acidosis or MERRF (myoclonic epilepsy with ragged red fibers), in addition to myopathy, exercise intolerance, muscle atrophy, ataxia, seizures, migraines, vomiting, sensorineural hearing loss, and pigmentary retinopathy. Heteroplasmy levels in affected individuals ranged from being undetectable in certain tissues to being present at homoplasmy. There was limited testing in family members precluding considering of segregation evidence. There is one report of a de novo occurrence (PMID: 1645537) however the ability to detect low levels of heteroplasmy was limited at the time. There are four heteroplasmic occurrences of this variant in the Helix dataset, and the variant is absent in the GenBank dataset and in gnomAD v3.1.2 (PM2_supporting). MitoTIP suggests this variant is likely benign (46.6 percentile) and HmtVAR predicts it a deleterious effect (0.65). Functional testing demonstrated this variant was associated with impaired tRNA modification (PS3_moderate). This variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent phenotypes in affected individuals and strong functional evidence showing impaired modification of the tRNA. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PS3_moderate.
Met criteria codes
PS3_Moderate
Functional testing demonstrated this variant was associated with impaired tRNA modification (PS3_moderate).
PS4_Moderate
The m.15923A>G variant in MT-TT has been reported in four individuals with primary mitochondrial disease from four unrelated families (PS4_moderate; PMIDs: 1645537, 22638997, 29760464, 30236074). Age of onset varied from the second day of life to the 50s. Affected individuals had features consistent with neonatal lactic acidosis or MERRF (myoclonic epilepsy with ragged red fibers), in addition to myopathy, exercise intolerance, muscle atrophy, ataxia, seizures, migraines, vomiting, sensorineural hearing loss, and pigmentary retinopathy. Heteroplasmy levels in affected individuals ranged from being undetectable in certain tissues to being present at homoplasmy.
PM2_Supporting
There are four heteroplasmic occurrences of this variant in the Helix dataset, and the variant is absent in the GenBank dataset and in gnomAD v3.1.2 (PM2_supporting).
Not Met criteria codes
PP1
There was limited testing in family members precluding considering of segregation evidence.
PP3
MitoTIP suggests this variant is likely benign (46.6 percentile) and HmtVAR predicts it a deleterious effect (0.65).
PM6
There is one report of a de novo occurrence (PMID: 1645537) however the ability to detect low levels of heteroplasmy was limited at the time.
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
There is one report of a de novo occurrence (PMID: 1645537) however the ability to detect low levels of heteroplasmy was limited at the time.
Curation History
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