rs199476122

Variant names:

• chrM-3697-G-A
• rs199476122
• ENST00000361390.2:c.391G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PS3_Supporting PP1_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.3697G>A (p.G131S) variant in MT-ND1 has been reported in at least 14 individuals with primary mitochondrial disease from 8 families. Affected individuals had onset ranging from the first week of life to adulthood; and with features variably consistent with Leigh syndrome, MELAS, and LHON (PS4_moderate; PMIDs: 31996177, 30623604, 28429146, 24830958, 18977334, 17562939, 15466014). There are no reports of de novo occurrence of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 24830958, 17562939, 16969869, 15466014). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Functional studies supported the deleterious impact of this variant (PS3_supporting; PMID:15466014). 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 March 22, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4_moderate, PM2_supporting, PP1_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120647/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.93
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 O:2 MELAS-/-Leigh-Syndrome-/-LDYT-/-BSN
• Conservation: PhyloP100: 7.56
• Publications: 40 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.
• PP1: 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

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND1	ENST00000361390.2	TSL:6	c.391G>A	p.Gly131Ser	missense	Exon 1 of 1	ENSP00000354687.2	P03886

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MELAS-/-Leigh-Syndrome-/-LDYT-/-BSN

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	MELAS syndrome (3)
1	-	-	Dystonic disorder;C0026826:Hypertonia;C0036572:Seizure;C0149931:Migraine;C1263846:Attention deficit hyperactivity disorder;C1836830:Developmental regression;C3278923:Ventriculomegaly (1)
1	-	-	Leber optic atrophy (2)
1	-	-	Leber optic atrophy and dystonia (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.93
Hmtvar	Pathogenic	0.85
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.11	D
DEOGEN2	Benign	0.26	T
LIST_S2	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.6
PROVEAN	Pathogenic	-5.4	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.83
Mutation Taster		=42/58	disease causing

Other links and lift over

dbSNP: rs199476122; hg19: chrM-3698; COSMIC: COSV62292949; COSMIC: COSV62292949;