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
  • The variant label for this record ("m.3260A>G") does not appear to be in HGVS format
  • No CSPEC computer assertion could be determined for this classification!

Variant: m.3260A>G

CA120566

9596 (ClinVar)

Gene: N/A
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
Link to MONDO
UUID: d6de9d84-02d5-4b9c-854c-04809379c14f
Approved on: 2023-05-22
Published on: 2024-07-23

HGVS expressions

NC_012920.1:m.3260A>G
J01415.2:m.3260A>G

Likely Pathogenic

Met criteria codes 5
PP1_Moderate PM2_Supporting PS3_Supporting PP3 PS4_Moderate

Evidence Links 2

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.3260A>G variant in MT-TL1 has been reported in five unrelated individuals with primary mitochondrial disease (PS4_moderate; PMIDs: 1677065, 8210299, 8941275, 20965148, 24656211). Three individuals had features variably consistent with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; PMIDs: 8941275, 20965148, 24656211) and two individuals had cardiomyopathy and skeletal muscle myopathy (PMIDs: 1677065, 8210299). There are no reported de novo occurrences to our knowledge. This variant segregated with disease in one of the reported families, as five affected family members had heteroplasmy levels ranging from 86% - 90% whereas unaffected family members had heteroplasmy levels ranging from 20% - 78% (PP1_moderate; PMID: 1677065). 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 (81st percentile) and HmtVAR predicts it to be pathogenic score of 0.7 (PP3). Studies in cybrids and yeast support the functional impact of this variant (PS3_supporting; PMIDs: 8132749, 19631764). 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 May 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3, PS3_supporting.
Met criteria codes
PP1_Moderate
This variant segregated with disease in one of the reported families, as five affected family members had heteroplasmy levels ranging from 86% - 90% whereas unaffected family members had heteroplasmy levels ranging from 20% - 78% (PP1_moderate; PMID: 1677065).
PM2_Supporting
This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
PS3_Supporting
Studies in cybrids and yeast support the functional impact of this variant (PS3_supporting; PMIDs: 8132749, 19631764).
In this cybrid study the presence and the amount of the G3260 mutation was shown to correlate with defective mitochondrial respiration examined by biochemical analysis of complex I- and complex IV-specific activities, oxygen consumption rate, and lactic acid production. The increase of lactic acid levels is a sensitive index of a block in the aerobic utilization of pyruvate. Oxygen consumption and lactate production were the most discriminating tests between the M and WT groups. PubMed:8132749
Yeast model equivalent to human m.3260A>G (strain A30(29)G) showed a delayed; growth and a lower plateau with respect to the WT (with the lowest growth rate for the MLeuA30(29)G mutant). The respiration; curves of MLeuA30(29)G cells also show a significant decrease in; O2 consumption, compared to the WT (fig 4). Transcripts extracted from MLeuA30(29)G mutant were aminoacylated, but the amount of tRNALeuUUR was strongly decreased. PMID 19631764. PubMed:19631764
PP3
The computational predictor MitoTIP suggests this variant is pathogenic (81st percentile) and HmtVAR predicts it to be pathogenic score of 0.7 (PP3).
PS4_Moderate
The m.3260A>G variant in MT-TL1 has been reported in five unrelated individuals with primary mitochondrial disease (PS4_moderate; PMIDs: 1677065, 8210299, 8941275, 20965148, 24656211). Three individuals had features variably consistent with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; PMIDs: 8941275, 20965148, 24656211) and two individuals had cardiomyopathy and skeletal muscle myopathy (PMIDs: 1677065, 8210299).
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