rs199476105

Variant names:

• chrM-14459-G-A
• rs199476105
• ENST00000361681.2:c.215C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM6 PS4 PS3_Supporting PP1_Moderate PP3

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120625/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Pathogenic 0.93
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:2 LDYT-/-Leigh-Disease-/-dystonia-/-carotid-atherosclerosis-risk
• Conservation: PhyloP100: 4.42
• Publications: 29 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]

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: Pathogenic. The variant received 10 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.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND6	ENST00000361681.2	TSL:6	c.215C>T	p.Ala72Val	missense	Exon 1 of 1	ENSP00000354665.2	P03923
	MT-TE	ENST00000387459.1	TSL:6	n.*215C>T		downstream_gene	N/A

Frequencies

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

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56432

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56432

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): LDYT-/-Leigh-Disease-/-dystonia-/-carotid-atherosclerosis-risk

Status: Cfrm-[P]

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Leber optic atrophy (4)
2	-	-	Leigh syndrome (3)
2	-	-	not provided (2)
1	-	-	Leber optic atrophy and dystonia (1)
1	-	-	Leigh syndrome due to mitochondrial complex I deficiency (1)
1	-	-	MELAS syndrome (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.4
PROVEAN	Uncertain	-4.0	D
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
GERP RS		4.0
Varity_R		0.32
Mutation Taster		=89/11	polymorphism

Other links and lift over

dbSNP: rs199476105; hg19: chrM-14460;