ENST00000361390.2:c.74G>A

Variant names:

• chrM-3380-G-A
• rs1603218926
• ENST00000361390.2:c.74G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000361390.2(MT-ND1):​c.74G>A​(p.Arg25Gln) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 2)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.83
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 MELAS
• Conservation: PhyloP100: 7.46
• Publications: 1 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]

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• PM2: Very low frequency in mitomap database: 0.0
• PP3: Apogee2 supports a deletorius effect, 0.82897216 >= 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.74G>A	p.Arg25Gln	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*76G>A		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*151G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.74G>A	p.Arg25Gln	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*76G>A		downstream_gene_variant		6
MT-RNR2	ENST00000387347.2	n.*151G>A		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0 AC: 2

Mitomap

Disease(s): MELAS

Status: Reported-[VUS]

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic: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.3380G>A (YP_003024026.1:p.Arg25Gln) 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 -

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.3380G>A (p.R25Q) variant in MT-ND1 has been reported in one individual with primary mitochondrial disease to date, in a 62-year-old woman with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) who also had adult-onset hearing loss (PMID: 18590963). Muscle biopsy showed ragged red fibers. The variant was present at 50% heteroplasmy in skeletal muscle and 5-10% in white blood cells. The variant was absent in blood in her three healthy sons. Single fiber testing in muscle from the proband showed higher levels of the variant in ragged red fibers (61.15%, n=13) than in non-ragged red fibers (29.5%, n=11), p<0.01 (PS3_supporting, PMID: 18590963). Additionally, decreased enzyme activity was seen when this variant was modeled in E. coli (PMID: 36431069). This variant is rare in population databases (MITOMAP: 0.003%, 2/61,883; absent in gnomAD v3.1.2 and Helix; PM2_supporting). The computational predictor APOGEE suggests this variant is pathogenic (0.65, range 0-1; PP3). 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): PS3_supporting, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.83
Hmtvar	Pathogenic	0.88
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.17	D
DEOGEN2	Uncertain	0.43	T
LIST_S2	Benign	0.85	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.5
PROVEAN	Uncertain	-3.6	D
Sift4G	Pathogenic	0.0	D
GERP RS		3.7
Varity_R		0.85

Other links and lift over

dbSNP: rs1603218926; hg19: chrM-3381; COSMIC: COSV62293468; COSMIC: COSV62293468;