ENST00000361381.2:c.1019G>A

Variant names:

• chrM-11778-G-A
• rs199476112
• ENST00000361381.2:c.1019G>A

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PS4 PP1_Moderate PS3_Supporting PP3

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: Mitomap GenBank: Absent
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Pathogenic 0.93
• Clinical Significance: Pathogenic reviewed by expert panel P:21 O:2 LHON-/-Progressive-Dystonia
• Conservation: PhyloP100: 3.76
• Publications: 100 publications found

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]

MT-ND4 Gene-Disease associations (from GenCC):

• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leber plus disease

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 8 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361381.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND4	ENST00000361381.2	TSL:6	c.1019G>A	p.Arg340His	missense	Exon 1 of 1	ENSP00000354961.2

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Gnomad homoplasmic AF: 0.00019 AC: 11 AN: 56423

Gnomad heteroplasmic AF: 0.00023 AC: 13 AN: 56423

Alfa AF: 0.000277 Hom.: 3

Mitomap

Disease(s): LHON-/-Progressive-Dystonia

Status: Cfrm-[P]

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
11	-	-	Leber optic atrophy (13)
4	-	-	not provided (4)
1	-	-	Leber optic atrophy and dystonia (1)
1	-	-	Leber optic atrophy, susceptibility to (1)
1	-	-	Mitochondrial disease (1)
1	-	-	not specified (1)
1	-	-	Optic atrophy (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.8
PROVEAN	Pathogenic	-4.7	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.6
Varity_R		0.22

Other links and lift over

dbSNP: rs199476112; hg19: chrM-11779;