chrM-14484-T-C

Position:

• chrM-14484-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PM2 PP5_Very_Strong BS2

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ND6 missense
• Scores: Apogee2 Pathogenic 0.90
• Clinical Significance: Pathogenic reviewed by expert panel P:12 O:3 LHON
• Conservation: PhyloP100: -1.48

Genes affected

ND6 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-14484-T-C is Pathogenic according to our data. Variant chrM-14484-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9688.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 30

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ND6	unassigned_transcript_4817	c.190A>G	p.Met64Val	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Gnomad homoplasmic AF: 0.00053 AC: 30 AN: 56427

Gnomad heteroplasmic AF: 0.00012 AC: 7 AN: 56427

Alfa AF: 0.000668 Hom.: 3

Mitomap

LHON

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:3

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:6 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 25, 2021	This variant was identified as homoplasmic -
Pathogenic, no assertion criteria provided	research	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Sep 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	This variant is one of the three most common causes of LHON. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported on 01-26-2018 by Lab or GTR ID 26957. 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	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 17, 2019	The NC_012920.1:m.14484T>C (YP_003024037.1:p.Met64Val) variant in MTND6 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	Aug 01, 2008	- -

not provided Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 12, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MT-ND6 p.Met64Val This is a well-known disease-causing variant that predisposes to Leber's hereditary optic neuropathy. It is one of the three most common variants for this disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 26, 2017	The m.14484T>C variant is one of three primary pathogenic LHON-causing variants, and is detected in 14% of reported LHON cases (Mackey 1996 and Man 2002). In certain ethnic groups, the proportion can be much higher, such as in individuals of French Canadian ancestry, where 79% of LHON pedigrees carry the m.14484T>C variant (Macmillan 1998). Macmillan (1998) also demonstrated that males carrying this variant are 7.7 times more likely to develop symptoms than females. The clinical presentation of mitochondrial diseases caused by mtDNA variants is highly variable and depends on the total percentage of abnormal mitochondria and tissue-specific distribution. The penetrance of the m.14484T>C variant is also influenced by age, and other environmental and genetic modifiers. -

Mitochondrial disease Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Sep 12, 2022

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. -

Optic atrophy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Retinal dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Leigh syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

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
PROVEAN	Benign	-2.0	N
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0020	D
GERP RS		-8.1
Varity_R		0.49

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476104; hg19: chrM-14485;