ENST00000361681.2:c.221C>T

Variant names:

• chrM-14453-G-A
• rs199476107
• ENST00000361681.2:c.221C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS4_Moderate PP3 PM2_Supporting PM6_Strong

This summary comes from the ClinGen Evidence Repository: The m.14453G>A (p.A74V) variant in MT-ND6 has been reported in at least 10 individuals with primary mitochondrial disease from 10 families. Affected individuals had onset ranging from the first day of life to adulthood (all but one case had early childhood onset, however); and with features variably consistent with Leigh syndrome and MELAS (PS4_moderate; PMIDs: 34933128, 22947169, 33644659, 32552696, 24642831, 21364701, 11781695). Heteroplasmy levels ranged from 41-83%. There are at least five reports of de novo occurrences of this variant (PM6_strong, score 2.5; PMIDs: 34933128, 33644659, 24642831, 11781695). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at 2% in blood, however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.81 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on June 27, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PM6_strong, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254853/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Pathogenic 0.84
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1 MELAS-/-Leigh-Disease
• Conservation: PhyloP100: 3.05
• Publications: 15 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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

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.221C>T	p.Ala74Val	missense	Exon 1 of 1	ENSP00000354665.2
	MT-TE	ENST00000387459.1	TSL:6	n.*221C>T		downstream_gene	N/A

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MELAS-/-Leigh-Disease

Status: Cfrm-[LP]

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	MELAS syndrome (3)
1	-	-	Leigh syndrome (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.84
Hmtvar	Pathogenic	0.85
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.11	D
DEOGEN2	Uncertain	0.60	D
LIST_S2	Uncertain	0.93	D
MutationAssessor	Benign	1.9	L
PhyloP100		3.1
PROVEAN	Uncertain	-3.9	D
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
GERP RS		4.0
Varity_R		0.42
Mutation Taster		=83/17	polymorphism

Other links and lift over

dbSNP: rs199476107; hg19: chrM-14454; COSMIC: COSV62378042; COSMIC: COSV62378042;