rs199476109

Variant names:

• chrM-14487-T-C
• rs199476109
• unassigned_transcript_4816:c.187A>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

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 0.95
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1 Dystonia-/-Leigh-Disease-/-ataxia-/-ptosis-/-epilepsy
• Conservation: PhyloP100: 3.75

Genes affected

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]

TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-14487-T-C is Pathogenic according to our data. Variant chrM-14487-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9694.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND6	unassigned_transcript_4816	c.187A>G	p.Met63Val	missense_variant	Exon 1 of 1
TRNE	unassigned_transcript_4817	c.*187A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	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.

Mitomap

Dystonia-/-Leigh-Disease-/-ataxia-/-ptosis-/-epilepsy

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome Pathogenic:1 Other:1

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.14487T>C (YP_003024037.1:p.Met63Val) 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, PS3 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Leigh syndrome due to mitochondrial complex I deficiency Pathogenic:1

Nov 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Aug 08, 2022

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.14487T>C (p.M63V) variant in MT-ND6 has been reported in at least 37 unrelated individuals with primary mitochondrial disease (PS4; PMIDs: 30741831, 33706792, 34223155, 32162843, 30461153, 30128709, 30095618, 28122886, 28429146, 27338358, 26530508, 23813926, 23463613, 24126373, 23847141, 23010433, 21364701, 21196529, 19062322, 18977334, 17535832, 16044424, 15625630, 15576045, 14595656, 14520668, 14684687, 20019223). Features seen in affected individuals include Leigh syndrome spectrum and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), as well as ataxia, dystonia, epilepsy, optic neuropathy, and ptosis. Heteroplasmy levels were variable in affected individuals as was age of onset (infancy to adulthood). 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: 14684687,17535832, 20019223, 24126373, 26530508, 28122886). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies have shown independent functional consequences (PS3_moderate) including almost undetectable rotenone-dependent oxygen consumption (PMID 14520668), an overproduction of reactive oxygen species (ROS, PMID 16337195), and decreased complex I activity corresponding with heteroplasmy levels as well as decreased levels of fully assembled complex I (PMID 14595656). 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 August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_moderate. -

Striatal necrosis, bilateral, with dystonia Pathogenic:1

Nov 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

MELAS syndrome Pathogenic:1

Dec 04, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v3.1.2 dataset. Predicted Consequence/Location: Mitochondrial variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 14520668). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MT-ND6 related disorder (ClinVar ID: VCV000009694). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 30741831, 32162843, 33706792, 34223155). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 14684687, 17535832, 20019223, 24126373, 26530508, 28122886). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Leber optic atrophy Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.95
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.50	T
DEOGEN2	Pathogenic	0.85	D
LIST_S2	Benign	0.86	D
MutationAssessor	Pathogenic	3.9	H
PROVEAN	Uncertain	-4.0	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.0
Varity_R		0.81

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476109; hg19: chrM-14488;