rs199476105

chrM-14459-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_Moderate PM2 PP3 PP5_Very_Strong

The ENST00000361681.2(MT-ND6):c.215C>T(p.Ala72Val) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Pathogenic 0.93
• Clinical Significance: Pathogenic reviewed by expert panel P:8 O:2 LDYT-/-Leigh-Disease-/-dystonia-/-carotid-atherosclerosis-risk
• Conservation: PhyloP100: 4.42

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript ENST00000361681.2 (MT-ND6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.92525274 >= 0.5 .
• PP5: Variant M-14459-G-A is Pathogenic according to our data. Variant chrM-14459-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9689.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND6	ENST00000361681.2	c.215C>T	p.Ala72Val	missense_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

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

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56432

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56432

Mitomap

LDYT-/-Leigh-Disease-/-dystonia-/-carotid-atherosclerosis-risk

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 15, 2006	- -
not provided, no classification provided	literature only	GeneReviews	-	This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status. -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

Leigh syndrome Pathogenic:2 Other:1

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.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 -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Feb 11, 2021	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). -

Leber optic atrophy and dystonia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 15, 2006

- -

Leigh syndrome due to mitochondrial complex I deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 15, 2006

- -

Mitochondrial disease Pathogenic:1

Pathogenic, reviewed by expert panel

curation

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

Nov 01, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.93
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.098	D
DEOGEN2	Uncertain	0.61	D
LIST_S2	Benign	0.83	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PROVEAN	Uncertain	-4.0	D
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
GERP RS		4.0
Varity_R		0.32

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476105; hg19: chrM-14460;