rs199476116

Variant names:

• chrM-5131-TAA-T
• rs199476116
• ENST00000361453.3:c.664_665delAA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4 PS2_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.5133_5134delAA variant in MT-ND2 has been reported in one individual from one family (PMID:12192017), in a male with exercise intolerance, ragged red fibers, and reduced complex I activity. The variant was present at 93% heteroplasmy (PMID:19273755). This variant was reported to have occurred on the paternal mitochondrial DNA as two haplogroups were reportedly present in the proband, one matching his mother’s haplogroup and the other matching his father’s, although the variant was not present in his mother or father (PS2_supporting, PMID:12192017). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). 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. This 2 base pair deletion starting at amino acid L221 in the MT-ND2 gene results in a stop codon at position 251 (L251Ter). This results in a truncated MT-ND2 gene product (PM4). Of note, this expert panel considered whether this variant should be reviewed for several reasons: (1) analysis of the mitochondrial genome was limited at the time of this report in 2002, raising concern on whether this variant was truly present in the proband or technical artifact; (2) it is possible the variant was present in the nuclear DNA but erroneously assigned to mitochondrial DNA; (3) nuclear DNA etiologies were not assessed in this proband; and (4) there are no other validated occurrences of paternal inheritance of mitochondrial DNA. However, this expert panel elected to review this variant with the current evidence and it meets criteria to be classified as uncertain significance 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 October 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS2_supporting, PM2_supporting, PM4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120641/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND2 ENST00000361453.3 frameshift
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 Exercise-intolerance-(EXIT)
• Conservation: PhyloP100: -1.04
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: 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.664_665delAA	p.Asn222fs	frameshift	Exon 1 of 1	ENSP00000355046.4

Frequencies

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

Mitomap

Disease(s): Exercise-intolerance-(EXIT)

Status: Reported-[VUS]

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
PhyloP100		-1.0

Other links and lift over

dbSNP: rs199476116; hg19: chrM-5132;