chrM-4810-G-A

Position:

• chrM-4810-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ND2 stop_retained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 EXIT-with-myalgia-&-ophthalmoplegia
• Conservation: PhyloP100: 7.75

Genes affected

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-4810-G-A is Pathogenic according to our data. Variant chrM-4810-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9720.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ND2	unassigned_transcript_4793	c.341G>A	p.Ter114Ter	stop_retained_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

EXIT-with-myalgia-&-ophthalmoplegia

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial complex I deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 22, 2005

- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Oct 09, 2023

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. -

Computational scores

Source: dbNSFP v4.3

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606888; hg19: chrM-4811;