rs797045055

Variant names:

• chrM-14597-A-G
• rs797045055
• unassigned_transcript_4816:c.77T>C

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 Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ND6 missense
• Scores: Apogee2 Pathogenic 0.63
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:2 LHON-/-LS
• Conservation: PhyloP100: 1.68

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]

CYTB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [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-14597-A-G is Pathogenic according to our data. Variant chrM-14597-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209173.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.77T>C	p.Ile26Thr	missense_variant	Exon 1 of 1
CYTB	unassigned_transcript_4818	c.-150A>G		upstream_gene_variant
TRNE	unassigned_transcript_4817	c.*77T>C		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

LHON-/-LS

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Dysarthria;C0013421:Dystonic disorder Pathogenic:1

Jan 22, 2014

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Likely pathogenicity based on finding it once in our laboratory de novo and 49% heteroplasmic in a 31-year-old male with profound and progressive generalized dystonia, dysarthria, prominent perivascular spaces. This same codon was affected in a family with Leber optic atrophy and hereditary spastic dystonia (PMID 8644732). -

Mitochondrial disease Pathogenic:1

Aug 14, 2023

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.14597A>G (p.I26T) variant in MT-ND6 has been reported in three unrelated individuals with primary mitochondrial disease (PS4_supporting; PMIDs: 31669237, 34045482, 26633545). Clinical features in affected individuals include Leber Hereditary Optic Neuropathy (LHON, PMID: 31669237, this 39-year-old man was in haplogroup T2 and heteroplasmy levels were 25% in blood, 76% in skin fibroblasts, and 87% in urine), Leigh syndrome and optic atrophy (PMID: 34045482, this was a Japanese boy with 91% heteroplasmy in skin fibroblasts), and dystonia, dysarthria and prominent perivascular spaces (PMID: 26633545; the heteroplasmy levels in this man were 49% although the tissue was not specified). The variant segregated with clinical features in at least one family (the variant was found at 66% in blood in the sister of the boy with Leigh syndrome and at 17% in his mother’s blood, however blood heteroplasmy was not reported for the proband; PMID: 34045482). The variant was reported to occur de novo in at least one case, however technical details and tissues tested were not provided (PMID: 26633545). This variant is present in population databases (absent in Mitomap GenBank sequences and gnomAD v3.1.2; one heteroplasmic occurrence in the Helix dataset; PM2_supporting). The computation predictor APOGEE predicts this variant to be deleterious (score 0.67 in APOGEE1 and 0.63 in APOGEE2; PP3). Cybrid studies support the functional impact of this variant (PS3_supporting; PMIDs: 34045482) as significantly reduced complex I activity, respiration rate, and ATP content in three cybrid fibroblast cell lines were demonstrated. Furthermore, complex I deficiency was noted in skin fibroblasts of an affected individual in whom nuclear DNA etiologies were excluded (PP4, PMID: 26741492). Complex I deficiency was also reported in muscle, however the activity of complex I was reported to be 0% in this tissue, raising concern for the validity of this result. A different amino acid change at this position has been reported (m.14596A>T, p.I26M), however this was classified as a variant of uncertain significance, precluding formal consideration of this as evidence of pathogenicity for the m.14597A>G (p.I26T) variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent biochemical phenotype, compelling functional validation, and that other nearby variants are highly concerning to be causative of primary mitochondrial disease. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 14, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PS4_supporting, PP3, PP4. -

not specified Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome Uncertain:1

Oct 17, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.14597A>G (YP_003024037.1:p.Ile26Thr) variant in MTND6 gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PM9, PP6, PP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.63
Hmtvar	Pathogenic	0.78
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.12	T
DEOGEN2	Uncertain	0.62	D
LIST_S2	Uncertain	0.97	D
MutationAssessor	Uncertain	2.8	M
PROVEAN	Pathogenic	-4.6	D
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
GERP RS		4.2
Varity_R		0.91

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045055; hg19: chrM-14598;