rs199476104

Variant names:

• chrM-14484-T-C
• rs199476104
• ENST00000361681.2:c.190A>G

Your query was ambiguous. Multiple possible variants found:

• chrM-14484-T-C
• chrM-14484-T-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS4 PM6_Supporting PM5 PP3 PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The m.14484T>C (p.M64V) variant in MT-ND6 has been reported in >50 unrelated individuals with primary mitochondrial disease (PS4). This variant is one of the three most common variants associated with Leber Hereditary Optic Neuropathy (LHON; PMID:20301353) and is associated with a less severe phenotype, with visual recovery seen in some individuals. The age of onset ranges from adolescence to adulthood. While most affected individuals with this variant have LHON, other features have been seen including migraines (PMID:12601121), tremor (PMID:8931573), multiple sclerosis (PMIDs: 10098545, 35773337), and cardiac involvement (PMIDs: 12807863, 22749828). This variant is consistently seen in the homoplasmic state (PMIDs: 9484365, 24508359, 28392196, PMID:9339703, 8659531, 7611298, 7604366, 7603534, 8071952, 7877803, 1463007, 1417830, 1732158, 2018041). Several extended families have been reported in the medical literature however family member testing was not performed or the variant was homoplasmic and thus prevented consideration for segregation evidence of pathogenicity. There is at least one de novo occurrence reported in the medical literature (PM6_supporting; PMID:9339703). Furthermore, the presence of this variant in individuals from different haplogroups suggests this variant occurred de novo in the ancestors of these individuals of different backgrounds. 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 0.95 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Other variants at this amino acid position leading to a different amino acid change are known disease-associated variants – m.14482C>G and m.14482C>A that both result in p.M64I (PM5). Multiple independent studies support the functional impact of this variant (PS3_moderate). Eleven cybrid studies revealed various effects including decreased ND6, ND1, and ND4L levels; decreased complex I activity; respiratory deficiency; diminished mitochondrial ATP production; reduced membrane potential; and increased production of reactive oxygen species (ROS). Cybrid cells also had increased apoptosis, autophagy, and mitophagy (PMIDs: 35567411, 25909222, 20943885, 19047048, 18806273, 15883259, 15342361, 12446713, 12379308, 35858578). 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 September 12, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4, PP3, PM5, PM6_supporting, PS3_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340932/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Pathogenic 0.90
• Clinical Significance: Pathogenic reviewed by expert panel P:14 O:3 LHON
• Conservation: PhyloP100: -1.48
• Publications: 56 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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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.190A>G	p.Met64Val	missense	Exon 1 of 1	ENSP00000354665.2	P03923
	MT-TE	ENST00000387459.1	TSL:6	n.*190A>G		downstream_gene	N/A

Frequencies

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

Gnomad homoplasmic AF: 0.00053 AC: 30 AN: 56427

Gnomad heteroplasmic AF: 0.00012 AC: 7 AN: 56427

Alfa AF: 0.000432 Hom.: 7

Mitomap

Disease(s): LHON

Status: Cfrm-[P]

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Leber optic atrophy (8)
4	-	-	not provided (4)
1	-	-	Leber optic atrophy and dystonia (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Optic atrophy (1)
1	-	-	Retinal dystrophy (1)
-	-	-	Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.90
Hmtvar	Pathogenic	0.80
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.47	T
DEOGEN2	Benign	0.39	T
LIST_S2	Benign	0.69	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-1.5
PROVEAN	Benign	-2.0	N
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0020	D
GERP RS		-8.1
Varity_R		0.49

Other links and lift over

dbSNP: rs199476104; hg19: chrM-14485;