rs199476115

Variant names:

• chrM-5244-G-A
• rs199476115
• ENST00000361453.3:c.775G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.5244G>A (p.G259S) variant in MT-ND2 has been reported in one family (PMID:1634041) with Leber Hereditary Optic Neuropathy (LHON), however individuals in this family also harbored other mitochondrial DNA variants also associated with LHON, making the association of this variant to the primary mitochondrial disease features in these individuals unclear. Furthermore, to our knowledge, nuclear genetic testing was not performed. There are no reports of large families with this variant segregating with disease. There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (77 percentile, PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). 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 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340940/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND2 ENST00000361453.3 missense
• Scores: Apogee2 Pathogenic 0.95
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1 LHON
• Conservation: PhyloP100: 5.45
• Publications: 11 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 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND2	unassigned_transcript_4793	c.775G>A	p.Gly259Ser	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND2	ENST00000361453.3	c.775G>A	p.Gly259Ser	missense_variant	Exon 1 of 1	6		ENSP00000355046.4

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): LHON

Status: Reported-[VUS]

ClinVar

Significance: Uncertain significance

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

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Oct 09, 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.5244G>A (p.G259S) variant in MT-ND2 has been reported in one family (PMID: 1634041) with Leber Hereditary Optic Neuropathy (LHON), however individuals in this family also harbored other mitochondrial DNA variants also associated with LHON, making the association of this variant to the primary mitochondrial disease features in these individuals unclear. Furthermore, to our knowledge, nuclear genetic testing was not performed. There are no reports of large families with this variant segregating with disease. There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (77 percentile, PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). 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 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.95
Hmtvar	Pathogenic	0.83
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.13	D
DEOGEN2	Benign	0.18	T
LIST_S2	Uncertain	0.97	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		5.4
PROVEAN	Pathogenic	-5.8	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.0
Varity_R		0.47
Mutation Taster		=45/55	disease causing

Other links and lift over

dbSNP: rs199476115; hg19: chrM-5245;