chrM-4681-T-C

Variant names:

• chrM-4681-T-C
• rs267606889
• ENST00000361453.3:c.212T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.4681T>C (p.L71P) variant in MT-ND2 has been reported in one individual with primary mitochondrial disease to date, in a boy with Leigh syndrome and generalized muscle atrophy (PMIDs: 16996290, 16738010). He had elevated blood and cerebrospinal fluid lactate. Complex I deficiency was noted in skin fibroblasts. The variant was present at >95% heteroplasmy in blood, muscle, and fibroblasts. The variant was absent in his mother although technology performed at the time was limited in detecting low heteroplasmy levels. This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting, note the single occurrence in MITOMAP is likely from the reported patient). The computational predictor APOGEE suggests this variant is pathogenic (0.52, range 0-1; PP3). Cybrid studies supported the functional impact of this variant as mutant cybrids had reduced complex I activity and impaired complex I assembly (PS3_supporting; PMID:16996290). In summary, this variant 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 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120644/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: MT-ND2 ENST00000361453.3 missense
• Scores: Apogee2 Pathogenic 0.73
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1 Leigh-Syndrome
• Conservation: PhyloP100: 7.63
• Publications: 10 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]

TRNM (HGNC:7492): (mitochondrially encoded tRNA methionine)

TRNM Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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: ENST00000361453.3. 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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND2	ENST00000361453.3	TSL:6	c.212T>C	p.Leu71Pro	missense	Exon 1 of 1	ENSP00000355046.4
	MT-TM	ENST00000387377.1	TSL:6	n.*212T>C		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0 AC: 1

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Leigh-Syndrome

Status: Reported-[VUS]

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome due to mitochondrial complex I deficiency Pathogenic:1

Nov 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mitochondrial disease Uncertain:1

Oct 23, 2023

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.4681T>C (p.L71P) variant in MT-ND2 has been reported in one individual with primary mitochondrial disease to date, in a boy with Leigh syndrome and generalized muscle atrophy (PMIDs: 16996290, 16738010). He had elevated blood and cerebrospinal fluid lactate. Complex I deficiency was noted in skin fibroblasts. The variant was present at >95% heteroplasmy in blood, muscle, and fibroblasts. The variant was absent in his mother although technology performed at the time was limited in detecting low heteroplasmy levels. This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting, note the single occurrence in MITOMAP is likely from the reported patient). The computational predictor APOGEE suggests this variant is pathogenic (0.52, range 0-1; PP3). Cybrid studies supported the functional impact of this variant as mutant cybrids had reduced complex I activity and impaired complex I assembly (PS3_supporting; PMID: 16996290). In summary, this variant 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 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting.

Leigh syndrome Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.73
Hmtvar	Pathogenic	0.89
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.000084	T
DEOGEN2	Benign	0.30	T
LIST_S2	Benign	0.58	T
MutationAssessor	Pathogenic	4.6	H
PhyloP100		7.6
PROVEAN	Uncertain	-4.3	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.3
Varity_R		0.93

Other links and lift over

dbSNP: rs267606889; hg19: chrM-4682;