rs199476112
Variant summary
Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PS4PP1_ModeratePS3_SupportingPP3
This summary comes from the ClinGen Evidence Repository: The m.11778G>A (p.R340H) variant in MT-ND4 has been reported in >16 unrelated individuals with primary mitochondrial disease. 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, affected individuals have been reported with features including LHON, Leigh syndrome, cerebellar ataxia, migraines, regression, leukoencephalopathy, myoclonus, psychiatric illness, Parkinsonism, axonal neuropathy, multiple sclerosis, and ophthalmoplegia; and this variant has been seen in affected individuals in the homoplasmic and heteroplasmic states (PS4; PMIDs: 3201231, 2575667, 2566021, 2390098, 1635296, 17724295, 18848389, 25917160, 18216301, 17254817, 8902729, 27119776). 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: 27119776, 2390098). There are no confirmed de novo occurrences of this variant to our knowledge. 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 0.97 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 10976107, 7763260). This variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common variants associated with LHON. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS3_supporting, PS4, PP1_moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340939/MONDO:0044970/014
Frequency
Consequence
ENST00000361381.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MT-ND4 | ENST00000361381.2 | c.1019G>A | p.Arg340His | missense_variant | 1/1 | ENSP00000354961 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Leber optic atrophy Pathogenic:11Other:2
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | - | A heteroplasmic (76.20%) missense variant has been identified in MT-ND4. This gene encodes a protein subunit of complex I. The variant is predicted to result in a minor amino acid change from arginine to histidine at position 340 of the protein. The arginine at this position has high conservation (MITOMASTER). In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, HmtDB Disease Score). The variant is present in the MITOMAP population database at a frequency of 0.358%. The variant has been previously described as pathogenic in multiple individuals with Leber hereditary optic neuropathy (LHON) and is considered to be the most common MT-ND4 variant in European and Asian populations. Affected individuals generally have more than 70% heteroplasmy in blood, however the variant is also known to have reduced penetrance, with males more commonly affected than females (ClinVar, GeneReviews, OMIM, PMID: 31932089). This variant has been shown to be maternally inherited (by trio analysis) with a heteroplamic level of 26.70% in this individual's mother. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Sep 16, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 17, 2019 | The NC_012920.1:m.11778G>A (YP_003024035.1:p.Arg340His) variant in MTND4 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS4 - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2008 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
| Pathogenic, no assertion criteria provided | research | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jun 26, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Pediatric Department, Xiangya Hospital, Central South University | - | - - |
| not provided, no classification provided | literature only | GeneReviews | - | This variant is one of the three most common causes of LHON. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 20, 2024 | Criteria applied: PS4,PP1_MOD,PS3_SUP,PP3 - |
| Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 12, 2017 | m.11778G>A is one of a small number of primary variants which are causative of Leber hereditary optic neuropathy (LHON; MIM: 535000). It is estimated that 70% of LHON families of northern European descent carry the m.11778G>A variant (Mackey 1996). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Nov 04, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jan 24, 2024 | - - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 22, 2022 | - - |
Mitochondrial disease Pathogenic:1
| Pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jun 30, 2022 | The m.11778G>A (p.R340H) variant in MT-ND4 has been reported in >16 unrelated individuals with primary mitochondrial disease. 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, affected individuals have been reported with features including LHON, Leigh syndrome, cerebellar ataxia, migraines, regression, leukoencephalopathy, myoclonus, psychiatric illness, Parkinsonism, axonal neuropathy, multiple sclerosis, and ophthalmoplegia; and this variant has been seen in affected individuals in the homoplasmic and heteroplasmic states (PS4; PMIDs: 3201231, 2575667, 2566021, 2390098, 1635296, 17724295, 18848389, 25917160, 18216301, 17254817, 8902729, 27119776). 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: 27119776, 2390098). There are no confirmed de novo occurrences of this variant to our knowledge. 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 0.97 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 10976107, 7763260). This variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common variants associated with LHON. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PS4, PP1_moderate, PP3. - |
Leber optic atrophy, susceptibility to Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | May 27, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at