M-10197-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_Moderate PM2 PP3 PP5_Very_Strong

The ENST00000361227.2(MT-ND3):c.139G>A(p.Ala47Thr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND3 ENST00000361227.2 missense
• Scores: Apogee2 Pathogenic 0.84
• Clinical Significance: Pathogenic reviewed by expert panel P:9 O:1 Leigh-Disease-/-Dystonia-/-Stroke-/-LDYT,Leigh-Disease
• Conservation: PhyloP100: 4.69

Genes affected

MT-ND3 (HGNC:7458): (mitochondrially encoded NADH dehydrogenase 3) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript ENST00000361227.2 (MT-ND3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.84368604 >= 0.5 .
• PP5: Variant M-10197-G-A is Pathogenic according to our data. Variant chrM-10197-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9715.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND3	ENST00000361227.2	c.139G>A	p.Ala47Thr	missense_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Alfa AF: 0.000223 Hom.: 0

Mitomap

Leigh-Disease-/-Dystonia-/-Stroke-/-LDYT,Leigh-Disease

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 17, 2019	The NC_012920.1:m.10197G>A (YP_003024033.1:p.Ala47Thr) variant in MTND3 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM9, PM10, PP4, PP6 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Pediatric Department, Xiangya Hospital, Central South University	-	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Sep 22, 2022

- -

Leber optic atrophy and dystonia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2009

- -

Mitochondrial disease Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Jul 25, 2022

The m.10197G>A (p.A47T) variant in MT-ND3 has been reported in at least 22 probands with primary mitochondrial disease. Affected individuals had variable ages of onset (first months of life to childhood to adulthood). Features included Leigh syndrome, Leigh syndrome/MELAS overlap, and LHON with good visual recovery. Heteroplasmy levels were variable among tissues and affected individuals, and ranged from 10% (in an individual with LHON) to homoplasmy (in an individual with Leigh syndrome; PS4; PMIDs: 15372108, 17152068, 17413873, 18977334, 19458970, 20818383, 20972245, 24708134, 30128709, 30199507, 30776730, 32045392; two articles with no PMIDs: Pereira et al., 2019; JIEMS, 2019, Vol7: e20180003; Huang et al., 2017, J Clin Exp Ophthalmol 2017, 8:4). 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: 17152068, 17413873, 30128709, 30776730). This variant occurred de novo in at least three individuals (PM6_moderate, PMIDs: 24708134, 17413873; article with no PMID: Huang et al., 2017, J Clin Exp Ophthalmol 2017, 8:4). There are four occurrences of this variant in the GenBank dataset, and three of these four are not listed as patient sequences. However, upon discussion on the Expert Panel (EP) call, concern was raised that phylogenetic studies use patient samples and submit these to GenBank. This variant is absent in gnomAD v3.1.2 and in Helix dataset so the EP agreed to consider this supporting line of evidence (PM2_supporting). Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I activity (PS3_supporting, PMID: 17152068). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.88 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as 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 July 25, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PP1_moderate, PS3_supporting, PM6_moderate, PS4. -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Jun 15, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 29, 2017

The m.10197G>A variant (rs267606891) affects the MT-ND3 gene involved in mitochondrial complex I (CI) function, and has been identified in several patients with symptoms of Leigh disease (LD), LD-like, dystonia, and/or other symptoms associated with CI dysfunction (see link to GeneReviews below). This variant was first identified by Kirby (2004), wherein a patient harboring this variant is described as having LD-like symptoms and was shown to have reduced CI activity in cultured fibroblasts. Subsequent studies have also identified this variant in a French family affected with LS (Sarzi 2007), a Korean family with basal ganglia lesions (Chae 2007), and a single individual with LS (Valente 2009). All affected individuals studied have also been shown to have reduced CI activity in cell culture. Also, when analyzed, the degree of heteroplasmy tracks with disease severity, with asymptomatic carriers showing reduced levels of variant load compared to affected patients. Additionally, this variant is rare in MITOMAP, and is not associated with any particular haplogroup. Therefore, the m.10197G>A variant satisfies our criteria for classification as pathogenic. -

Mitochondrial complex 1 deficiency, mitochondrial type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2009

- -

Mitochondrial DNA-Associated Leigh Syndrome and NARP Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.84
Hmtvar	Pathogenic	0.79
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.22	T
DEOGEN2	Uncertain	0.53	D
LIST_S2	Benign	0.82	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	3.2e-7	A
PROVEAN	Uncertain	-3.5	D
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.1
Varity_R		0.22

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606891; hg19: chrM-10198;