M-4810-G-A

Variant names:

• chrM-4810-G-A
• rs267606888
• ENST00000361453.3:c.341G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PS3_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.4810G>A (p.W114*) variant in MT-ND2 has been reported in three individuals with primary mitochondrial disease to date. One individual was reported to have severe exercise intolerance, muscle weakness, myalgia, ophthalmoplegia, ptosis, elevated blood lactate, elevated CK, electromyography consistent with myopathy, and ragged red fibers on muscle biopsy (PMID:15781840). Complex I activity was reduced in muscle. The variant was present at 94% heteroplasmy in muscle and was undetectable in blood. The two additional individuals reported had ophthalmoplegia and ptosis, however no additional details were provided (Roisin 2022, Newcastle University, https://theses.ncl.ac.uk/jspui/bitstream/10443/5737/1/Stout%20R%20B%202022.pdf). There are no reported de novo occurrences of this variant to our knowledge. There are no reports of large families with this variant segregating with disease. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The transition at base position m.4810 causes a W114Ter change. This causes a significant truncation (67%) of the ND2 protein (PVS1_strong). Single fiber testing showed numerous ragged-red fibers with the variant present at a mean of 84.27% (n=15) compared to the variant being present at a mean heteroplasmy of 7.15% in the normal fibers (n=14, PS3_supporting, PMID:15781840). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that one expert on this panel felt uncertain significance was the more appropriate classification given only one case with clinical details has been reported and extensive functional validation is lacking. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PS3_supporting, PVS1_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120642/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND2 ENST00000361453.3 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 EXIT-with-myalgia-&-ophthalmoplegia
• Conservation: PhyloP100: 7.75
• Publications: 2 publications found

Genes affected

MT-ND2 (HGNC:7456): (mitochondrially encoded NADH dehydrogenase 2) 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; multiple sclerosis; myocardial infarction; neurodegenerative disease (multiple); and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

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

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

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361453.3. 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-ND2	ENST00000361453.3	TSL:6	c.341G>A	p.Trp114*	stop_gained	Exon 1 of 1	ENSP00000355046.4	P03891

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): EXIT-with-myalgia-&-ophthalmoplegia

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex I deficiency (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
PhyloP100		7.8
GERP RS		3.6

Other links and lift over

dbSNP: rs267606888; hg19: chrM-4811;