ENST00000361390.2:c.584G>A

Variant names:

• chrM-3890-G-A
• rs587776434
• ENST00000361390.2:c.584G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4_Moderate PP1_Moderate PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.3890G>A (p.R195Q) variant in MT-ND1 has been reported in at least nine individuals from nine families in the literature, who had features falling within the Leber Hereditary Optic Neuropathy (LHON) or Leigh syndrome spectrums (PS4_moderate; PMIDs: 34390870, 33337510, 27798429, 18504678, 30095618, 23246842, 23847141). There are no reports of de novo occurrence of this variant to our knowledge. Although this variant most often is seen in the homoplasmic state, in one multi-generational family, there were five unaffected relatives with low heteroplasmy levels in urine and blood, compared to much higher levels in the proband (PP1_moderate; PMID 2324842). This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (one occurrence in GenBank sequences is from individual with mitochondrial disease – PMID:23246842; variant absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.73 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies showed that the homoplasmic mutant clones had statistically significant decreases in Complex I and ATP synthesis activities (PS3_supporting, PMID:23246842). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on March 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP1_moderate, PS4_moderate, PP3, PM2_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA345911/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.93
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1 Progressive-Encephalomyopathy-/-Leigh-Syndrome-/-Optic-Atrophy
• Conservation: PhyloP100: 3.88
• Publications: 14 publications found

Genes affected

MT-ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND1 Gene-Disease associations (from GenCC):

• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

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

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

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

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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
ND1	unassigned_transcript_4789	c.584G>A	p.Arg195Gln	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.584G>A	p.Arg195Gln	missense_variant	Exon 1 of 1	6		ENSP00000354687.2

Frequencies

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

Mitomap

Disease(s): Progressive-Encephalomyopathy-/-Leigh-Syndrome-/-Optic-Atrophy

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Pathogenic:1

Sep 22, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Pathogenic:1

Jun 30, 2022

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.3890G>A (p.R195Q) variant in MT-ND1 has been reported in at least nine individuals from nine families in the literature, who had features falling within the Leber Hereditary Optic Neuropathy (LHON) or Leigh syndrome spectrums (PS4_moderate; PMIDs: 34390870, 33337510, 27798429, 18504678, 30095618, 23246842, 23847141). There are no reports of de novo occurrence of this variant to our knowledge. Although this variant most often is seen in the homoplasmic state, in one multi-generational family, there were five unaffected relatives with low heteroplasmy levels in urine and blood, compared to much higher levels in the proband (PP1_moderate; PMID 2324842). This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (one occurrence in GenBank sequences is from individual with mitochondrial disease – PMID: 23246842; variant absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.73 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies showed that the homoplasmic mutant clones had statistically significant decreases in Complex I and ATP synthesis activities (PS3_supporting, PMID: 23246842). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on March 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PS4_moderate, PP3, PM2_supporting, PS3_supporting. -

Leigh syndrome Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.93
Hmtvar	Pathogenic	0.82
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.21	D
DEOGEN2	Uncertain	0.48	T
LIST_S2	Uncertain	0.87	D
MutationAssessor	Pathogenic	5.0	H
PhyloP100		3.9
PROVEAN	Uncertain	-3.8	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.82

Other links and lift over

dbSNP: rs587776434; hg19: chrM-3891;