ClinVar Miner

Submissions for variant NC_012920.1(MT-ND1):m.3460G>A

dbSNP: rs199476118
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen RCV003319165 SCV004023282 pathogenic Mitochondrial disease 2023-04-25 reviewed by expert panel curation 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757484 SCV000885731 pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing m.3460G>A is one of a small number of primary variants which are causative of Leber hereditary optic neuropathy (LHON; MIM: 535000; Howell 1992). It is estimated that 15%-25% of LHON families carry the g.3460G>A variant (Howell 1991).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000010370 SCV000996688 pathogenic Leber optic atrophy 2019-10-17 criteria provided, single submitter clinical testing The NC_012920.1:m.3460G>A (YP_003024026.1:p.Ala52Thr) variant in MTND1 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000757484 SCV001447466 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Mendelics RCV000010370 SCV002517662 pathogenic Leber optic atrophy 2022-05-04 criteria provided, single submitter clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000757484 SCV005199257 pathogenic not provided 2022-10-04 criteria provided, single submitter clinical testing
OMIM RCV000010370 SCV000030596 pathogenic Leber optic atrophy 2007-07-10 no assertion criteria provided literature only
GeneReviews RCV000010370 SCV000086632 not provided Leber optic atrophy no assertion provided literature only This variant is one of the three most common causes of LHON.
GeneReviews RCV000143998 SCV000188884 not provided Leigh syndrome no assertion provided literature only
OMIM RCV000735416 SCV000863528 pathogenic MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 3 2007-07-10 no assertion criteria provided literature only
Genomics England Pilot Project, Genomics England RCV000010370 SCV001760534 pathogenic Leber optic atrophy no assertion criteria provided clinical testing

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