Submissions for variant NC_012920.1(MT-ND6):m.14484T>C

dbSNP: rs199476104

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV003162238	SCV003915445	pathogenic	Mitochondrial disease	2022-09-12	reviewed by expert panel	curation	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000223709	SCV000604296	pathogenic	not provided	2017-05-26	criteria provided, single submitter	clinical testing	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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000010325	SCV000998163	pathogenic	Leber optic atrophy	2019-10-17	criteria provided, single submitter	clinical testing	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
Institute of Human Genetics, University of Leipzig Medical Center	RCV000010325	SCV001950062	pathogenic	Leber optic atrophy	2021-08-25	criteria provided, single submitter	clinical testing	This variant was identified as homoplasmic
Mendelics	RCV000010325	SCV002517680	pathogenic	Leber optic atrophy	2022-05-04	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000010325	SCV002580430	pathogenic	Leber optic atrophy	2021-10-18	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000223709	SCV005196604	pathogenic	not provided	2022-10-04	criteria provided, single submitter	clinical testing
OMIM	RCV000010325	SCV000030551	pathogenic	Leber optic atrophy	2008-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000010325	SCV000086625	not provided	Leber optic atrophy		no assertion provided	literature only	This variant is one of the three most common causes of LHON.
GeneReviews	RCV000144018	SCV000188910	not provided	Leigh syndrome		no assertion provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223709	SCV000280192	likely pathogenic	not provided	2015-06-12	no assertion criteria provided	clinical testing	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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000010325	SCV000993415	pathogenic	Leber optic atrophy	2018-09-25	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000010325	SCV001338881	not provided	Leber optic atrophy		no assertion provided	phenotyping only	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.