rs199476122

Variant names:

• chrM-3697-G-A
• rs199476122
• unassigned_transcript_4789:c.391G>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: Absent
• Consequence: ND1 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

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: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-3697-G-A is Pathogenic according to our data. Variant chrM-3697-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9733.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.391G>A	p.Gly131Ser	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

MELAS-/-Leigh-Syndrome-/-LDYT-/-BSN

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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.3697G>A (YP_003024026.1:p.Gly131Ser) 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, PM8, PM9, PM10 -

Jun 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leber optic atrophy Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber optic atrophy and dystonia Pathogenic:1

Jun 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Mar 24, 2022

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.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. -

Dystonic disorder;C0026826:Hypertonia;C0036572:Seizure;C0149931:Migraine;C1263846:Attention deficit hyperactivity disorder;C1836830:Developmental regression;C3278923:Ventriculomegaly Pathogenic:1

Aug 18, 2021

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

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
PROVEAN	Pathogenic	-5.4	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.83

Splicing

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

Publications

LitVar

Other links and lift over

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