ENST00000361681.2:c.187A>G

Variant names:

• chrM-14487-T-C
• rs199476109
• ENST00000361681.2:c.187A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS4 PP1_Moderate PP3 PM2_Supporting PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The m.14487T>C (p.M63V) variant in MT-ND6 has been reported in at least 37 unrelated individuals with primary mitochondrial disease (PS4; PMIDs: 30741831, 33706792, 34223155, 32162843, 30461153, 30128709, 30095618, 28122886, 28429146, 27338358, 26530508, 23813926, 23463613, 24126373, 23847141, 23010433, 21364701, 21196529, 19062322, 18977334, 17535832, 16044424, 15625630, 15576045, 14595656, 14520668, 14684687, 20019223). Features seen in affected individuals include Leigh syndrome spectrum and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), as well as ataxia, dystonia, epilepsy, optic neuropathy, and ptosis. Heteroplasmy levels were variable in affected individuals as was age of onset (infancy to adulthood). 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: 14684687,17535832, 20019223, 24126373, 26530508, 28122886). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies have shown independent functional consequences (PS3_moderate) including almost undetectable rotenone-dependent oxygen consumption (PMID 14520668), an overproduction of reactive oxygen species (ROS, PMID 16337195), and decreased complex I activity corresponding with heteroplasmy levels as well as decreased levels of fully assembled complex I (PMID 14595656). 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 August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120627/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Pathogenic 0.95
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1 Dystonia-/-Leigh-Disease-/-ataxia-/-ptosis-/-epilepsy
• Conservation: PhyloP100: 3.75
• Publications: 22 publications found

Genes affected

MT-ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]

TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

TRNE Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 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.
• PM2: 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: ENST00000361681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND6	ENST00000361681.2	TSL:6	c.187A>G	p.Met63Val	missense	Exon 1 of 1	ENSP00000354665.2	P03923
	MT-TE	ENST00000387459.1	TSL:6	n.*187A>G		downstream_gene	N/A

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Dystonia-/-Leigh-Disease-/-ataxia-/-ptosis-/-epilepsy

Status: Cfrm-[P]

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Leber optic atrophy (1)
1	-	-	Leigh syndrome (2)
1	-	-	Leigh syndrome due to mitochondrial complex I deficiency (1)
1	-	-	MELAS syndrome (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Striatal necrosis, bilateral, with dystonia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.95
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.50	T
DEOGEN2	Pathogenic	0.85	D
LIST_S2	Benign	0.86	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		3.8
PROVEAN	Uncertain	-4.0	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.0
Varity_R		0.81
Mutation Taster		=90/10	polymorphism

Other links and lift over

dbSNP: rs199476109; hg19: chrM-14488;