rs199476123

Variant names:

• chrM-3946-G-A
• rs199476123
• ENST00000361390.2:c.640G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PS3_Supporting PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254862/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.86
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 O:1 MELAS
• Conservation: PhyloP100: 9.44
• Publications: 26 publications found

Genes affected

MT-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]

MT-ND1 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
• mitochondrial complex I deficiency

  Inheritance: AR 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 6 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361390.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND1	ENST00000361390.2	TSL:6	c.640G>A	p.Glu214Lys	missense	Exon 1 of 1	ENSP00000354687.2

Frequencies

Mitomap GenBank AF: 0.0 AC: 1

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MELAS

Status: Reported-[LP]

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	MELAS syndrome (4)
2	-	-	Leber optic atrophy (2)
1	-	-	Leigh syndrome (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.4
PROVEAN	Uncertain	-3.8	D
Sift4G	Uncertain	0.0050	D
GERP RS		4.5
Varity_R		0.93

Other links and lift over

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