M-3949-T-C

Variant names:

• chrM-3949-T-C
• rs199476124
• ENST00000361390.2:c.643T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM6_Supporting PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.3949T>C (p.Y215H) variant in MT-ND1 has been reported in one individual to date with primary mitochondrial disease. This individual had features consistent with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and harbored the variant at 93% heteroplasmy in muscle, 45% in blood, and 88% in fibroblasts (PMID:15466014). This variant occurred de novo in one individual (absent in blood from mother and two brothers; PM6_supporting, PMID:15466014). Electron transport chain (ETC) enzyme activity in fibroblasts and muscles was consistent with severe isolated defect of complex I, and levels of assembled complex I was approximately 12% of control; however, nuclear etiologies were not excluded (PMID:15466014). 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.3949GT>C variant is present in Mitomap’s GenBank dataset at less than 1/50,000 or 0.002% (1/61,168 sequences, 0.00163%, haplogroup K1a). 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 0.54 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance 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): PM6_supporting, PS3_supporting, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254863/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.64
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1 MELAS
• Conservation: PhyloP100: 7.58
• Publications: 7 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: Uncertain_significance. The variant received 4 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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: 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.643T>C	p.Tyr215His	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-[VUS]

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	MELAS syndrome (2)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.64
Hmtvar	Pathogenic	0.84
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.031	T
DEOGEN2	Benign	0.23	T
LIST_S2	Benign	0.81	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.6
PROVEAN	Pathogenic	-4.7	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.93
Mutation Taster		=45/55	disease causing

Other links and lift over

dbSNP: rs199476124; hg19: chrM-3950;