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rs199476112

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 13P and 4B. PS1_ModeratePM2PP3PP5_Very_StrongBS2

The ENST00000361381.2(MT-ND4):c.1019G>A(p.Arg340His) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Mitomap GenBank:
Absent

Consequence

MT-ND4
ENST00000361381.2 missense

Scores

Apogee2
Pathogenic
0.93

Clinical Significance

Pathogenic reviewed by expert panel P:17O:2
LHON-/-Progressive-Dystonia

Conservation

PhyloP100: 3.76
Variant links:
Genes affected
MT-ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS1
Transcript ENST00000361381.2 (MT-ND4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
No frequency data in Mitomap. Probably very rare.
PP3
Apogee2 supports a deletorius effect, 0.9260422 >= 0.5 .
PP5
Variant M-11778-G-A is Pathogenic according to our data. Variant chrM-11778-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9708.Status of the report is reviewed_by_expert_panel, 3 stars.
BS2
High AC in GnomadMitoHomoplasmic at 11

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MT-ND4ENST00000361381.2 linkuse as main transcriptc.1019G>A p.Arg340His missense_variant 1/1 P1

Frequencies

GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Gnomad homoplasmic
AF:
0.00019
AC:
11
AN:
56423
Gnomad heteroplasmic
AF:
0.00023
AC:
13
AN:
56423
Alfa
AF:
0.000111
Hom.:
0

Mitomap

LHON-/-Progressive-Dystonia

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:17Other:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Leber optic atrophy Pathogenic:11Other:2
not provided, no classification providedliterature onlyGeneReviews-This variant is one of the three most common causes of LHON. -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2008- -
Pathogenic, no assertion criteria providedresearchEquipe Genetique des Anomalies du Developpement, Université de BourgogneJun 26, 2018- -
Pathogenic, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineOct 17, 2019The 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, criteria provided, single submitterclinical testingPediatric Department, Xiangya Hospital, Central South University-- -
Pathogenic, no assertion criteria providedclinical testingGenomics England Pilot Project, Genomics England-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterFeb 01, 2024Criteria applied: PS4,PM5,PP1_MOD,PS3_SUP,PP3 -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Pathogenic, criteria provided, single submitterclinical testingVictorian 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. -
not provided, no classification providedphenotyping onlyGenomeConnect, 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 submitterclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics Laboratory, University Hospital Schleswig-HolsteinSep 16, 2021- -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMay 12, 2017m.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 submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsNov 04, 2014- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin BerlinSep 22, 2022- -
Mitochondrial disease Pathogenic:1
Pathogenic, reviewed by expert panelcurationClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGenJun 30, 2022The 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 submitterclinical testingMGZ Medical Genetics CenterMay 27, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
0.93
Hmtvar
Pathogenic
0.85
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Benign
-0.29
T
DEOGEN2
Benign
0.24
T
LIST_S2
Uncertain
0.87
D
MutationAssessor
Pathogenic
5.1
H
MutationTaster
Benign
0.000055
A
PROVEAN
Pathogenic
-4.7
D
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
GERP RS
4.6
Varity_R
0.22

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199476112; hg19: chrM-11779; API