rs587776433

Variant names:

• chrM-3481-G-A
• rs587776433
• ENST00000361390.2:c.175G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS3_Supporting PP3 PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.3481G>A (p.E59K) variant in MT-ND1 has been reported in at least two unrelated individuals. The first, an 8-year-old male with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), exhibited muscle weakness, ragged red fibers on muscle biopsy, multiple acute encephalopathic episodes, and rod-cone-type retinal dystrophy. Heteroplasmy ranged from 50%-80% (PMID:17535832). The second individual was a female with severe developmental delay, spastic tetraparesis, joint contractures, type 2 fiber atrophy seen on muscle biopsy, severe visual impairment, and epilepsy with onset at 6 months. She developed hypertrophic cardiomyopathy at 16 years old and died from cardiac insufficiency at 26. Heteroplasmy ranged from 12%-61% (PMID:18504678). Both individuals had elevated lactate and abnormalities on brain MRI. This variant may have been observed in a third individual with mitochondrial epilepsy; however the full text was unavailable for review (PMID:31665838). Haplogroup information was not reported for all cases precluding consideration for PS4. In the family of the proband with MELAS, the proband exhibited heteroplasmy levels ranging from 50-80% (lymphocytes: 55%). However, unaffected or less severely affected maternal relatives, including the mother, maternal aunt, and maternal cousin (who reported migraines), displayed lower heteroplasmy levels ranging from 15-20% in lymphocytes (PP1, PMID:17535832). In the other case, the variant was absent in mother’s blood (PMID:18504678), however the proband's blood was not tested. Complex I deficiency was demonstrated in both probands, however nuclear causes of disease were not excluded (PMIDs: 17535832, 18504678). Cybrid studies demonstrated a strong inverse correlation between heteroplasmy level and Complex I activity (PS3_supporting, PMID:17535832). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic with raw scores of 0.69 and 0.754, respectively (Min=0, Max=1), which predict a damaging effect on gene function (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. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP1, PS3_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA345910/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.89
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:2 MELAS-/-Progressive-Encephalomyopathy
• Conservation: PhyloP100: 7.62
• Publications: 9 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]

TRNL1 (HGNC:7490): (mitochondrially encoded tRNA leucine 1 (UUA/G)) Implicated in cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

TRNL1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE, LIMITED Submitted by: G2P, ClinGen
• maternally-inherited diabetes and deafness

  Inheritance: Mitochondrial Classification: STRONG Submitted by: Genomics England PanelApp
• MERRF 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.

• PS3: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361390.2. 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-ND1	ENST00000361390.2	TSL:6	c.175G>A	p.Glu59Lys	missense	Exon 1 of 1	ENSP00000354687.2
	MT-TL1	ENST00000386347.1	TSL:6	n.*177G>A		downstream_gene	N/A

Frequencies

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

Mitomap

Disease(s): MELAS-/-Progressive-Encephalomyopathy

Status: Cfrm-[LP]

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:1 Other:1

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.3481G>A (YP_003024026.1:p.Glu59Lys) variant in MTND1 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS3, PM8, PM9, PP4, PP6

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Mitochondrial disease Uncertain:1

Sep 26, 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.3481G>A (p.E59K) variant in MT-ND1 has been reported in at least two unrelated individuals. The first, an 8-year-old male with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), exhibited muscle weakness, ragged red fibers on muscle biopsy, multiple acute encephalopathic episodes, and rod-cone-type retinal dystrophy. Heteroplasmy ranged from 50%-80% (PMID:17535832). The second individual was a female with severe developmental delay, spastic tetraparesis, joint contractures, type 2 fiber atrophy seen on muscle biopsy, severe visual impairment, and epilepsy with onset at 6 months. She developed hypertrophic cardiomyopathy at 16 years old and died from cardiac insufficiency at 26. Heteroplasmy ranged from 12%-61% (PMID: 18504678). Both individuals had elevated lactate and abnormalities on brain MRI. This variant may have been observed in a third individual with mitochondrial epilepsy; however the full text was unavailable for review (PMID:31665838). Haplogroup information was not reported for all cases precluding consideration for PS4. In the family of the proband with MELAS, the proband exhibited heteroplasmy levels ranging from 50-80% (lymphocytes: 55%). However, unaffected or less severely affected maternal relatives, including the mother, maternal aunt, and maternal cousin (who reported migraines), displayed lower heteroplasmy levels ranging from 15-20% in lymphocytes (PP1, PMID: 17535832). In the other case, the variant was absent in mother’s blood (PMID: 18504678), however the proband's blood was not tested. Complex I deficiency was demonstrated in both probands, however nuclear causes of disease were not excluded (PMIDs: 17535832, 18504678). Cybrid studies demonstrated a strong inverse correlation between heteroplasmy level and Complex I activity (PS3_supporting, PMID: 17535832). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic with raw scores of 0.69 and 0.754, respectively (Min=0, Max=1), which predict a damaging effect on gene function (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. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PS3_supporting, PM2_supporting, PP3.

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	0.89
Hmtvar	Pathogenic	0.84
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.18	D
DEOGEN2	Benign	0.31	T
LIST_S2	Uncertain	0.94	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.6
PROVEAN	Uncertain	-3.6	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.8
Varity_R		0.94

Other links and lift over

dbSNP: rs587776433; hg19: chrM-3482;