rs199476123

Variant names:

• chrM-3946-G-A
• rs199476123
• unassigned_transcript_4789:c.640G>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: 𝑓 0.0 (AC: 1)
• Consequence: ND1 missense
• Scores: Apogee2 Pathogenic 0.86
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 O:1 MELAS
• Conservation: PhyloP100: 9.44

Genes affected

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP5: Variant M-3946-G-A is Pathogenic according to our data. Variant chrM-3946-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.640G>A	p.Glu214Lys	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 GenBank AF: 0.0 AC: 1

Mitomap

MELAS

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:3 Other:1

Aug 05, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 07, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PS4_MOD,PM2_SUP,PP3 -

Oct 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leber optic atrophy Pathogenic:2

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome 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.3946G>A (YP_003024026.1:p.Glu214Lys) variant in MTND1 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS3 -

Mitochondrial disease Pathogenic:1

Aug 22, 2023

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.3946G>A (p.E214K) variant in MT-ND1 has been reported in at least five unrelated individuals with features of a primary mitochondrial disease. Affected individuals had variable ages of onset (first few months of life to mid-teenage years). Features were variable but consistent with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), complex seizure disorder, or Leigh syndrome. Heteroplasmy ranged from 45% to 66% in fibroblasts or muscle (PS4_moderate; PMIDs: 26741492, 15466014, 31996177, 24105702). The variant was not detected in the blood or urine sediment of the mother in one case, however these tissues differed from that tested in the proband (PMID: 24105702). Electron transport chain (ETC) enzyme activities were assessed in multiple unrelated affected individuals with non-diagnostic exome sequencing and chromosomal microarray. Two individuals had major combined complex deficiency (Pt619 and Pt640; PMID: 26741492). An additional individual had approximately 20% residual activity in fibroblasts compared to controls, a 40%–60% decrease in mature complex I levels, reduced levels of MT-ND1 protein, and normal MT-ND1 mRNA levels (PP4; PMID: 24105702). Studies in E. coli (PMID: 16849371) and cybrids (PMID: 15466014) support the functional impact of this variant, and independent studies showed independent deleterious effects of the variant (PS3_supporting). The m.3946G>A variant is present in Mitomap’s GenBank dataset at less than 1/50,000 or 0.002% (1/61,168 sequences, 0.00163%, haplogroup L0f). This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.66 (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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP4, PS3_supporting, PP3, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.86
Hmtvar	Pathogenic	0.91
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.23	D
DEOGEN2	Uncertain	0.46	T
LIST_S2	Uncertain	0.91	D
MutationAssessor	Pathogenic	4.6	H
PROVEAN	Uncertain	-3.8	D
Sift4G	Uncertain	0.0050	D
GERP RS		4.5
Varity_R		0.93

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476123; hg19: chrM-3947; COSMIC: COSV62293794; COSMIC: COSV62293794;