rs587776433

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000361390.2(MT-ND1):​c.175G>A​(p.Glu59Lys) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 7/11 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• 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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 5 uncertain in ENST00000361390.2
• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.89338267 >= 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.175G>A	p.Glu59Lys	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*177G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.175G>A	p.Glu59Lys	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*177G>A		downstream_gene_variant		6

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 -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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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

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

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;