chrM-11777-C-A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS4_Moderate PS3_Supporting PM5 PP3 PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.11777C>A (p.R340S) variant in MT-ND4 has been reported in at least eight unrelated individuals with primary mitochondrial disease and features including Leigh syndrome, stroke-like episodes, and cardiomyopathy (PS4_moderate; PMIDs: 12707444, 16120329, 15576045, 20502985, 24642831, 29428506). Ages of onset varied from the first few days of life to the 60s and heteroplasmy levels in affected individuals ranged from 50-93%. There is one report of the variant being absent in mother’s blood (PMID:16120329) however no additional tissues were tested and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. This variant segregated with disease in one family, as two healthy family members had lower to undetectable levels of the variant (PP1; PMID:20502985). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Another variant at this amino acid position leading to a different amino acid change is a known pathogenic variant – m.11778G>A (p.R340H, PM5). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID:16120329). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.83 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic 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 May 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PP1, PS3_supporting, PM2_supporting, PM5, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120636/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Pathogenic 0.89
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1 Leigh-Disease
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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: 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>A	p.Arg340Ser	missense	Exon 1 of 1	ENSP00000354961.2	P03905

Frequencies

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

Mitomap

Disease(s): Leigh-Disease

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Leber optic atrophy (1)
1	-	-	Leber optic atrophy and dystonia (1)
1	-	-	Mitochondrial complex I deficiency (1)
1	-	-	Mitochondrial disease (1)
-	-	-	Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.89
Hmtvar	Pathogenic	0.84
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.27	T
DEOGEN2	Benign	0.21	T
LIST_S2	Uncertain	0.93	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		4.5
PROVEAN	Pathogenic	-5.7	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.6
Varity_R		0.79
Mutation Taster		=21/79	disease causing (ClinVar)

Other links and lift over

dbSNP: rs28384199; hg19: chrM-11778;