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.14487T>C") does not appear to be in HGVS format

Variant: m.14487T>C

CA120627

9694 (ClinVar)

Gene: MT-ND6
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
Link to MONDO
UUID: 8f02e73d-8506-43b1-b27b-13c3ac0f8dc7

HGVS expressions

NC_012920.1:m.14487T>C
J01415.2:m.14487T>C
ENST00000361681.2:n.187A>G

Pathogenic

Met criteria codes 5
PP1_Moderate PS4 PM2_Supporting PP3 PS3_Moderate

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.14487T>C (p.M63V) variant in MT-ND6 has been reported in at least 37 unrelated individuals with primary mitochondrial disease (PS4; PMIDs: 30741831, 33706792, 34223155, 32162843, 30461153, 30128709, 30095618, 28122886, 28429146, 27338358, 26530508, 23813926, 23463613, 24126373, 23847141, 23010433, 21364701, 21196529, 19062322, 18977334, 17535832, 16044424, 15625630, 15576045, 14595656, 14520668, 14684687, 20019223). Features seen in affected individuals include Leigh syndrome spectrum and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), as well as ataxia, dystonia, epilepsy, optic neuropathy, and ptosis. Heteroplasmy levels were variable in affected individuals as was age of onset (infancy to adulthood). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 14684687,17535832, 20019223, 24126373, 26530508, 28122886). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies have shown independent functional consequences (PS3_moderate) including almost undetectable rotenone-dependent oxygen consumption (PMID 14520668), an overproduction of reactive oxygen species (ROS, PMID 16337195), and decreased complex I activity corresponding with heteroplasmy levels as well as decreased levels of fully assembled complex I (PMID 14595656). In summary, this variant meets criteria to be classified as 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 August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_moderate.
Met criteria codes
PP1_Moderate
This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 14684687,17535832, 20019223, 24126373, 26530508, 28122886).
PS4
The m.14487T>C (p.M63V) variant in MT-ND6 has been reported in at least 37 unrelated individuals with primary mitochondrial disease (PS4; PMIDs: 30741831, 33706792, 34223155, 32162843, 30461153, 30128709, 30095618, 28122886, 28429146, 27338358, 26530508, 23813926, 23463613, 24126373, 23847141, 23010433, 21364701, 21196529, 19062322, 18977334, 17535832, 16044424, 15625630, 15576045, 14595656, 14520668, 14684687, 20019223). Features seen in affected individuals include Leigh syndrome spectrum and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), as well as ataxia, dystonia, epilepsy, optic neuropathy, and ptosis. Heteroplasmy levels were variable in affected individuals as was age of onset (infancy to adulthood).
PM2_Supporting
This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
PP3
The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).
PS3_Moderate
Cybrid studies have shown independent functional consequences (PS3_moderate) including almost undetectable rotenone-dependent oxygen consumption (PMID 14520668), an overproduction of reactive oxygen species (ROS, PMID 16337195), and decreased complex I activity corresponding with heteroplasmy levels as well as decreased levels of fully assembled complex I (PMID 14595656).
Complex I-deficient fibroblasts were transiently co-cultured with bone marrow-derived MSCs. Co-culturing of complex I-deficient fibroblasts with MSC mitochondria lowered cellular ROS levels [and] significantly improved mitochondrial respiration, indicating a mitigation of the oxidative phosphorylation defect. PubMed:35715829
Approved on: 2022-08-08
Published on: 2023-03-29
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