rs797045055

Variant names:

• chrM-14597-A-G
• rs797045055
• ENST00000361681.2:c.77T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PS3_Supporting PP3 PP4 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA250381/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Pathogenic 0.63
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:2 LHON-/-LS
• Conservation: PhyloP100: 1.68
• Publications: 2 publications found

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]

MT-CYB (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)

TRNE Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 5 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND6	ENST00000361681.2	TSL:6	c.77T>C	p.Ile26Thr	missense	Exon 1 of 1	ENSP00000354665.2
	MT-CYB	ENST00000361789.2	TSL:6	c.-150A>G		upstream_gene	N/A	ENSP00000354554.2
	MT-TE	ENST00000387459.1	TSL:6	n.*77T>C		downstream_gene	N/A

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Mitomap

Disease(s): LHON-/-LS

Status: Cfrm-[LP]

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Dysarthria;C0013421:Dystonic disorder (1)
-	1	-	Leigh syndrome (1)
1	-	-	Mitochondrial disease (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.7
PROVEAN	Pathogenic	-4.6	D
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
GERP RS		4.2
Varity_R		0.91
Mutation Taster		=81/19	polymorphism

Other links and lift over

dbSNP: rs797045055; hg19: chrM-14598;