ENST00000361381.2:c.1018C>G

Variant names:

• chrM-11777-C-G
• rs28384199
• ENST00000361381.2:c.1018C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The ENST00000361381.2(MT-ND4):​c.1018C>G​(p.Arg340Gly) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R340S) has been classified as Likely pathogenic.

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Pathogenic 0.81
• Clinical Significance: Not reported in ClinVar No linked disesase in Mitomap
• Conservation: PhyloP100: 4.53
• Publications: 9 publications found

Genes affected

MT-ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND4 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
• Leber plus disease

  Inheritance: Mitochondrial 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrM-11777-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 9711.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Apogee2 supports a deletorius effect, 0.8122745 >= 0.5 .

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361381.2. 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-ND4	ENST00000361381.2	TSL:6	c.1018C>G	p.Arg340Gly	missense	Exon 1 of 1	ENSP00000354961.2	P03905

Frequencies

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

Mitomap

No disease associated.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.81
Hmtvar	Pathogenic	0.81
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.27	T
DEOGEN2	Benign	0.23	T
LIST_S2	Uncertain	0.95	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		4.5
PROVEAN	Pathogenic	-6.6	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
GERP RS		4.6
Varity_R		0.55

Other links and lift over

dbSNP: rs28384199; hg19: chrM-11778;