M-11777-C-A

Variant names:

• chrM-11777-C-A
• rs28384199
• unassigned_transcript_4811:c.1018C>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ND4 missense
• Scores: Apogee2 Pathogenic 0.89
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1 Leigh-Disease
• Conservation: PhyloP100: 4.53

Genes affected

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-11777-C-A is Pathogenic according to our data. Variant chrM-11777-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9711.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND4	unassigned_transcript_4811	c.1018C>A	p.Arg340Ser	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

Leigh-Disease

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy and dystonia Pathogenic:1

Nov 10, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v3.1.2 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on the gene or the gene product [APOGEE: 0.83 (>0.75 Likely pathogenic)] Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009711). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Mitochondrial complex I deficiency Pathogenic:1

Apr 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Jun 30, 2022

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Leber optic atrophy 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.11777C>A (YP_003024035.1:p.Arg340Ser) variant in MTND4 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, PP3, PP4, PP6 -

Leigh syndrome Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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
PROVEAN	Pathogenic	-5.7	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.6
Varity_R		0.79

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28384199; hg19: chrM-11778;