ENST00000361381.2:c.708A>G

Variant names:

• chrM-11467-A-G
• rs2853493
• ENST00000361381.2:c.708A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The m.11467A>G (p.L236L) variant in MT-ND4 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on January 13, 2025. This variant has not been reported in the medical literature as causative in affected individuals or families with primary mitochondrial disease to our knowledge. This variant is present at high frequencies in population databases (13% of individuals in MITOMAP, 16% in gnomAD v3.1.2, and 20% in the Helix dataset; BA1). Furthermore, this variant is a marker for European haplogroups U and K, where it is found at >99%, however the presence of this variant in an individual with primary mitochondrial disease outside of haplogroups U and K may warrant further consideration to rule out any detrimental effect of the variant. There are no in silico predictors for this type of variant in mitochondrial DNA. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as benign 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 January 13, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA337099193/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.13 (AC: 7901)
• Consequence: MT-ND4 ENST00000361381.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:4 Altered-brain-pH-/-sCJD-patients
• Conservation: PhyloP100: -3.03
• Publications: 31 publications found

Genes affected

MT-ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND4 Gene-Disease associations (from GenCC):

• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leber plus disease

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361381.2. 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-ND4	ENST00000361381.2	TSL:6	c.708A>G	p.Leu236Leu	synonymous	Exon 1 of 1	ENSP00000354961.2	P03905

Frequencies

Mitomap GenBank AF: 0.13 AC: 7901

Gnomad homoplasmic AF: 0.16 AC: 8766 AN: 56343

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56343

Alfa AF: 0.115 Hom.: 1283

Mitomap

Disease(s): Altered-brain-pH-/-sCJD-patients

Status: Reported

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Mitochondrial disease (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.0
Mutation Taster		=29/71	disease causing

Other links and lift over

dbSNP: rs2853493; hg19: chrM-11468; COSMIC: COSV62294568; COSMIC: COSV62294568;