Submissions for variant m.14459G>A

dbSNP: rs199476105

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV001796715	SCV002037593	pathogenic	Mitochondrial disease	2021-11-01	reviewed by expert panel	curation	The m.14459G>A (p.A72V) variant in MT-ND6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with variable features ranging from Leber Hereditary Optic Neuropathy (LHON) with or without dystonia, Leigh syndrome, bilateral basal ganglia lesions, ataxia, and migraines (PS4; PMIDs: 8016139, 7654063, 16380132, 10894222, 14735584, 21749722, 14735585, 28503604, 32045392, 29408632, 22426787). This variant has been identified as a de novo occurrence in at least 2 probands with primary mitochondrial disease (PM6; PMIDs: 14735584, 10894222). This variant heteroplasmy level segregated with severity in six family members from four families (PP1_moderate; PMIDs: 22426787, 21749722, 7654063, 8016139). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.93 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies supported the functional impact of this variant including a deficiency seen in patient cell line that was transferred to cybrids with a high mutant load and study was reproducible (PS3_supporting; PMID: 8622678). 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 U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6, PP1_moderate, PP3, PS3_supporting.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000144019	SCV000998157	pathogenic	Leigh syndrome	2019-10-17	criteria provided, single submitter	clinical testing	The NC_012920.1:m.14459G>A (YP_003024037.1:p.Ala72Val) variant in MTND6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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, PM9, PM10, PP4, PP6
Breda Genetics srl	RCV000144019	SCV001482520	pathogenic	Leigh syndrome	2021-02-11	criteria provided, single submitter	clinical testing	The variant m.14459G> A (p.Ala72Val) in the MT-ND6 gene is reported as pathogenic for Leigh syndrome and Leber hereditary optic neuropathy (LHON) in ClinVar (Variation ID: 9689) and is cited as pathogenic mutation in MITOMAP. The variant was identified in three out of 51836 sequences of the entire mitochondrial DNA (frequency 0.006%, GenBank, MITOMAP). This variant has previously been reported in patients with phenotypes ranging from Leigh or Leigh-like syndrome to Leber Hereditary Optic Neuropathy (LHON) plus dystonia, pure dystonia, pure LHON, or clinically asymptomatic. Jun et al. (1994) identified the variant m.14459G> A in heteroplasmy in a family with LHON and dystonia. Shoffner et al. (1995) identified the m.14459G> A mutation in a mother and daughter with isolated LHON (the daughter also had unilateral basal ganglia lesions on MRI). Kirby et al. (2000) identified the homoplasmic variant m.14459G> A in 3 patients with Leigh syndrome in whom there was no evidence of LHON or dystonia. Gropman and colleagues (2004) identified the m.14459G> A variant in a family with a broad spectrum of clinical manifestations. The proband presented with anarthria, dystonia, spasticity, and mild encephalopathy; MRI showed symmetrical and bilateral hyperintense lesions in the basal ganglia associated with cerebral and systemic lactic acidosis. Among other family members with the mutation, some were asymptomatic and others were symptomatic with varying clinical and laboratory characteristics, confirming the heterogeneous phenotype of this mutation even within the same family (OMIM * 516006).
Mendelics	RCV000010327	SCV002517679	pathogenic	Leber optic atrophy	2022-05-04	criteria provided, single submitter	clinical testing
OMIM	RCV000010326	SCV000030552	pathogenic	Leber optic atrophy and dystonia	2006-04-15	no assertion criteria provided	literature only
OMIM	RCV000010327	SCV000030553	pathogenic	Leber optic atrophy	2006-04-15	no assertion criteria provided	literature only
OMIM	RCV000010328	SCV000030554	pathogenic	Leigh syndrome due to mitochondrial complex I deficiency	2006-04-15	no assertion criteria provided	literature only
GeneReviews	RCV000010327	SCV000086622	not provided	Leber optic atrophy		no assertion provided	literature only	This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status.
GeneReviews	RCV000144019	SCV000188911	not provided	Leigh syndrome		no assertion provided	literature only
Genomics England Pilot Project, Genomics England	RCV000010327	SCV001760533	pathogenic	Leber optic atrophy		no assertion criteria provided	clinical testing