rs199476118
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS4PM6_SupportingPP1_ModeratePP3PS3_Moderate
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CV9722/MONDO:0044970/014
Frequency
Consequence
ENST00000361390.2 missense
Scores
Clinical Significance
Conservation
Publications
- mitochondrial diseaseInheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ND1 | unassigned_transcript_4789 | c.154G>A | p.Ala52Thr | missense_variant | Exon 1 of 1 | |||
| TRNL1 | unassigned_transcript_4788 | c.*156G>A | downstream_gene_variant | |||||
| RNR2 | unassigned_transcript_4787 | n.*231G>A | downstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MT-ND1 | ENST00000361390.2 | c.154G>A | p.Ala52Thr | missense_variant | Exon 1 of 1 | 6 | ENSP00000354687.2 | |||
| MT-TL1 | ENST00000386347.1 | n.*156G>A | downstream_gene_variant | 6 | ||||||
| MT-RNR2 | ENST00000387347.2 | n.*231G>A | downstream_gene_variant | 6 |
Frequencies
Mitomap
ClinVar
Submissions by phenotype
Leber optic atrophy Pathogenic:4Other:1
This variant is one of the three most common causes of LHON.
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
not provided Pathogenic:3
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).
Leber optic atrophy and dystonia Pathogenic:1
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (heteroplasmic allele frequency: 0.002%). Predicted Consequence/Location: Mitochondrial variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 1959619). The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (3billion dataset/ClinVar ID: VCV000009722). A different missense change at the same codon (p.Ala52Val) has been reported as pathogenic/likely pathogenic with strong evidence (Mitomap PMID: 32355048). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Mitochondrial disease Pathogenic:1
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.
Optic atrophy Pathogenic:1
MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 3 Pathogenic:1
Leigh syndrome Other:1
Computational scores
Source: