rs397515612

Variant names:

• chrM-3376-G-A
• rs397515612
• ENST00000361390.2:c.70G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. BP4 PS2_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.3376G>A (p.E24K) variant in MT-ND1 has been reported in one individual to date with primary mitochondrial disease. This individual had features in the MELAS/LHON spectrums and harbored the variant at 98% heteroplasmy in muscle, 18% in blood, and 67% in urine. This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals. This variant was de novo in the single reported case, as the proband's mother and siblings did not have the variant in blood or urine via PCR-RFLP (PS2_supporting; PMID:15657614). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of neutral with a borderline pathogenicity predictor score, 0.5 (Min=0, Max=1), evidence that does not predict a damaging effect on gene function (BP4). There are no cybrids or single fiber studies reported on this variant. 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 Mitochondrial Disease Variant Curation Expert Panel on February 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria (PMID:32906214): PS2_supporting, PM2_supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA345259/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.94
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 O:1 LHON-MELAS-overlap
• Conservation: PhyloP100: 6.32
• Publications: 26 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 1 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND1	ENST00000361390.2	TSL:6	c.70G>A	p.Glu24Lys	missense	Exon 1 of 1	ENSP00000354687.2	P03886
	MT-TL1	ENST00000386347.1	TSL:6	n.*72G>A		downstream_gene	N/A
	MT-RNR2	ENST00000387347.2	TSL:6	n.*147G>A		downstream_gene	N/A

Frequencies

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

Mitomap

Disease(s): LHON-MELAS-overlap

Status: Cfrm-[VUS*]

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial disease (1)
-	-	-	Leber optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.94
Hmtvar	Pathogenic	0.94
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.15	D
DEOGEN2	Uncertain	0.46	T
LIST_S2	Uncertain	0.94	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		6.3
PROVEAN	Uncertain	-3.6	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.72

Other links and lift over

dbSNP: rs397515612; hg19: chrM-3377;