Submissions for variant NC_012920.1(MT-ND4):m.11778G>A

dbSNP: rs199476112

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV002260593	SCV002540737	pathogenic	Mitochondrial disease	2022-06-30	reviewed by expert panel	curation	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224219	SCV000281600	pathogenic	not provided	2014-11-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224219	SCV000604440	pathogenic	not provided	2017-05-12	criteria provided, single submitter	clinical testing	m.11778G>A is one of a small number of primary variants which are causative of Leber hereditary optic neuropathy (LHON; MIM: 535000). It is estimated that 70% of LHON families of northern European descent carry the m.11778G>A variant (Mackey 1996).
Fulgent Genetics, Fulgent Genetics	RCV000010354	SCV000894486	pathogenic	Leber optic atrophy	2018-10-31	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000010354	SCV000997789	pathogenic	Leber optic atrophy	2019-10-17	criteria provided, single submitter	clinical testing	The NC_012920.1:m.11778G>A (YP_003024035.1:p.Arg340His) variant in MTND4 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 Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000224219	SCV001447248	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000010354	SCV001745880	pathogenic	Leber optic atrophy		criteria provided, single submitter	clinical testing
Mendelics	RCV000010354	SCV002517671	pathogenic	Leber optic atrophy	2022-05-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000010354	SCV002526724	pathogenic	Leber optic atrophy	2024-02-01	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM5,PP1_MOD,PS3_SUP,PP3
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV002285007	SCV002574880	pathogenic	not specified	2022-09-22	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288481	SCV002580016	pathogenic	Leber optic atrophy, susceptibility to	2022-05-27	criteria provided, single submitter	clinical testing
Pediatric Department, Xiangya Hospital, Central South University	RCV000010354	SCV002761214	pathogenic	Leber optic atrophy		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000010354	SCV003922001	pathogenic	Leber optic atrophy		criteria provided, single submitter	clinical testing	A heteroplasmic (76.20%) missense variant has been identified in MT-ND4. This gene encodes a protein subunit of complex I. The variant is predicted to result in a minor amino acid change from arginine to histidine at position 340 of the protein. The arginine at this position has high conservation (MITOMASTER). In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, HmtDB Disease Score). The variant is present in the MITOMAP population database at a frequency of 0.358%. The variant has been previously described as pathogenic in multiple individuals with Leber hereditary optic neuropathy (LHON) and is considered to be the most common MT-ND4 variant in European and Asian populations. Affected individuals generally have more than 70% heteroplasmy in blood, however the variant is also known to have reduced penetrance, with males more commonly affected than females (ClinVar, GeneReviews, OMIM, PMID: 31932089). This variant has been shown to be maternally inherited (by trio analysis) with a heteroplamic level of 26.70% in this individual's mother.
OMIM	RCV000010354	SCV000030580	pathogenic	Leber optic atrophy	2008-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000010354	SCV000086616	not provided	Leber optic atrophy		no assertion provided	literature only	This variant is one of the three most common causes of LHON.
GenomeConnect, ClinGen	RCV000010354	SCV000784691	not provided	Leber optic atrophy		no assertion provided	phenotyping only	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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000010354	SCV000993412	pathogenic	Leber optic atrophy	2018-06-26	no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV000010354	SCV001760532	pathogenic	Leber optic atrophy		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000010354	SCV002011706	pathogenic	Leber optic atrophy	2021-09-16	no assertion criteria provided	clinical testing