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
  • Gene listed was thus derived from ClinVar and/or CAR


Variant: NC_012920.1:m.3460G>A

9722 (ClinVar)

Gene: MT-ND1
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
UUID: 56afc669-34e6-4f09-9065-ca12c73f2299
Approved on: 2023-04-25
Published on: 2023-05-19

HGVS expressions

NC_012920.1:m.3460G>A

Pathogenic

Met criteria codes 5
PS4 PP3 PP1_Moderate PM6_Supporting PS3_Moderate
Not Met criteria codes 1
PM2

Evidence Links 6

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.3460G>A (p.A52T) variant in MT-ND1 has been reported in affected individuals from more than 50 kindreds (PS4, PMIDs: 1928099, 1674640, 7629530, 1734726, 1550131, 8496715, 8024249, 8556281, 8571959, 12205655, 11906302, 12807863, 12518276, 16738010, 17122117, 18216301, 18562849, 20232220, 21887510, 25338955, 25053773, 28314831, 30053855, 30591017). While this variant is one of the three most common variants associated with Leber Hereditary Optic Neuropathy (LHON; PMID: 20301353), affected individuals can also have other features. Indeed, several individuals have been reported with multiple sclerosis. Other features have been variably seen in affected individuals including sensorineural hearing loss, auditory neuropathy, epilepsy, migraines, Parkinsonism, dystonia, Leigh syndrome, spinal cord lesions, myoclonus, myopathy, hypertension, high triglycerides, diabetes, and cardiac involvement. Testing excluding separate etiologies for these features has been limited. Heteroplasmy levels in affected individuals ranged from 58% to homoplasmy. Age of onset varied from four years old to 75 years old. 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: 1734726, 8571959, 11906302). There is one reported de novo occurrence to our knowledge (PM6_supporting; PMID: 12518276). This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.86 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Extensive cybrid studies supported the functional impact of this variant, as do E. coli and mouse studies (PS3_moderate PMIDs: 35383288, 22079202, 15720387, 15883259, 15342361, 10976107). 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 April 25, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM6_supporting, PP3, PS3_moderate.
Met criteria codes
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.86 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).
PP1_Moderate
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6_Supporting
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3_Moderate
Not Met criteria codes
PM2
In the MITOMAP GenBank sequences, 16/31 occurrences are from LHON patients (0.02%). The variant is absent in gnomAD v.3.1.2. There are 14 heteroplasmic occurrences (across different haplogroups) in Helix (0.007%).
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