rs28384199

chrM-11777-C-AchrM-11777-C-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The ENST00000361381.2(MT-ND4):c.1018C>A(p.Arg340Ser) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R340H) has been classified as Likely pathogenic.

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Pathogenic 0.89
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 O:1 Leigh-Disease
• Conservation: PhyloP100: 4.53

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: Apogee2 supports a deletorius effect, 0.89304805 >= 0.5 .
• 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/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND4	ENST00000361381.2	c.1018C>A	p.Arg340Ser	missense_variant	1/1			P1

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:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial complex I deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1996

- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Jun 30, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Oct 17, 2019

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

not provided, no classification provided

literature only

GeneReviews

-

- -

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
MutationTaster	Benign	4.9e-7	A
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;