chrM-10158-T-C

Position:

• chrM-10158-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2_Supporting PM6_Strong PS4 PS3_Supporting PP3 PP1

This summary comes from the ClinGen Evidence Repository: The m.10158T>C (p.S34P) variant in MT-ND3 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID:32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood and who had features variably consistent with Leigh syndrome, MELAS and MELAS-like, and/or lactic acidosis (PS4; PMID:14705112; PMID:14684687; PMID:27348141; PMID:28050007; PMID:27742419; PMID:28916229; PMID:14764913; PMID:22115768; PMID:15576045; PMID:30128709; PMID:29237403; PMID:31178082; https://doi.org/10.1111/ncn3.17). This variant has been identified as a de novo occurrence in at least seven probands with primary mitochondrial disease (PM6_strong; PMID:28916229; PMID:14764913; PMID:14705112; PMID:14684687; PMID:31178082). This variant segregated with disease in multiple members in at least two families (PP1; PMID:27742419; PMID:14705112) and one healthy mother was found to have the variant at low heteroplasmy level (PMID:14705112). This variant is absent from Mitomap's GenBank sequences and gnomAD v3.1.2 (PM2_Supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies showed tight correlation between variant heteroplasmy level and complex I activity (PS3_supporting; PMID:14705112). 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 U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM2_supporting, PM6_strong, PP1, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA120639/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND3 ENST00000361227.2 missense
• Scores: Apogee2 Pathogenic 0.84
• Clinical Significance: Pathogenic reviewed by expert panel P:5 O:1 Leigh-Disease-/-MELAS
• Conservation: PhyloP100: -2.59

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 12 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.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ND3	ENST00000361227.2	c.100T>C	p.Ser34Pro	missense_variant	1/1			ENSP00000355206	P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

Leigh-Disease-/-MELAS

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 16, 2017	The m.10158T>C variant (rs199476117) 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; see link to GeneReviews below). For example, this variant was identified as a presumed de novo variant in the three independent families affected with LD as assessed by McFarland et al (2004). Cells isolated from patients harboring this variant had reduced levels of fully assembled complex I, and cybrid cell lines generated with the m.10158T>C variant had a reduction in complex I activity concomitant with the degree of heteroplasmy in individual established lines (McFarland 2004). Additional LD patients carrying this variant have also been described (Bugiani 2004 and Valente2009), whereas m.10158T>C is absent from the general population (MITOMAP). Therefore, the m.10158T>C variant satisfies our criteria for classification as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2014	- -

Leigh syndrome Pathogenic:1 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.10158T>C (YP_003024033.1:p.Ser34Pro) 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, PM8, PM9, PM10 -

Mitochondrial disease Pathogenic:1

Pathogenic, reviewed by expert panel

curation

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

Oct 26, 2021

The m.10158T>C (p.S34P) variant in MT-ND3 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood and who had features variably consistent with Leigh syndrome, MELAS and MELAS-like, and/or lactic acidosis (PS4; PMID: 14705112; PMID: 14684687; PMID: 27348141; PMID: 28050007; PMID: 27742419; PMID: 28916229; PMID: 14764913; PMID: 22115768; PMID: 15576045; PMID: 30128709; PMID: 29237403; PMID: 31178082; https://doi.org/10.1111/ncn3.17). This variant has been identified as a de novo occurrence in at least seven probands with primary mitochondrial disease (PM6_strong; PMID: 28916229; PMID: 14764913; PMID: 14705112; PMID: 14684687; PMID: 31178082). This variant segregated with disease in multiple members in at least two families (PP1; PMID: 27742419; PMID: 14705112) and one healthy mother was found to have the variant at low heteroplasmy level (PMID: 14705112). This variant is absent from Mitomap's GenBank sequences and gnomAD v3.1.2 (PM2_Supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies showed tight correlation between variant heteroplasmy level and complex I activity (PS3_supporting; PMID: 14705112). 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 U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM2_supporting, PM6_strong, PP1, PP3). -

Mitochondrial complex 1 deficiency, mitochondrial type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.84
Hmtvar	Pathogenic	0.40
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.41	T
DEOGEN2	Uncertain	0.44	T
LIST_S2	Uncertain	0.86	D
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	6.3e-12	A
PROVEAN	Benign	-2.1	N
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.015	D
GERP RS		-10
Varity_R		0.31

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476117; hg19: chrM-10159;