M-10191-T-C

Position:

• chrM-10191-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2_Supporting PM6_Strong PS4 PS3_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The m.10191T>C (p.S45P) variant in MT-ND3 has been reported in at least 30 unrelated individuals with primary mitochondrial disease. Of note, to our knowledge, all reported individuals have been the only affected person in the family. Affected individuals had variable ages of onset (birth to 20s) and outcomes (death in first month of life to alive in 20s at the time of report). Features included Leigh syndrome, MELAS-like syndrome, and Leigh/MELAS overlap, as well as epilepsia partialis continua (EPC) and optic atrophy. Heteroplasmy levels ranged from 13%-100% in affected individuals (PS4; PMIDs: 11456298, 14684687, 15576045, 14705112, 16044424, 16023078, 17535832, 18078792, 19135620, 19617458, 19520270, 20691940, 20226758, 20972245, 22364517, 28429146, 27450679, 30128709, 31261379). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at 3% in blood (PMID:11456298), however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant was seen in the mother’s blood in two other families (36% heteroplasmy in PMID:16044424; 5% in mother’s blood and undetectable in maternal grandmother’s blood in PMID:16023078), however no clinical details were provided on these family members to know if they were healthy or affected. There are at least six reports of de novo occurrences of this variant (PM6_strong; PMIDs: 14705112, 18078792, 19520270, 22364517, 27450679). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID:14705112). 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). 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 August 23, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PP3, PS3_supporting, PM6_strong, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120637/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND3 ENST00000361227.2 missense
• Scores: Apogee2 Pathogenic 0.89
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:1 Leigh-Disease-/-ESOC
• Conservation: PhyloP100: 3.31

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 11 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.
• 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.133T>C	p.Ser45Pro	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-/-ESOC

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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.10191T>C (YP_003024033.1:p.Ser45Pro) 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 -

Mitochondrial complex I deficiency Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genomics England Pilot Project, Genomics England

-

- -

Mitochondrial disease Pathogenic:1

Pathogenic, reviewed by expert panel

curation

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

Aug 23, 2022

The m.10191T>C (p.S45P) variant in MT-ND3 has been reported in at least 30 unrelated individuals with primary mitochondrial disease. Of note, to our knowledge, all reported individuals have been the only affected person in the family. Affected individuals had variable ages of onset (birth to 20s) and outcomes (death in first month of life to alive in 20s at the time of report). Features included Leigh syndrome, MELAS-like syndrome, and Leigh/MELAS overlap, as well as epilepsia partialis continua (EPC) and optic atrophy. Heteroplasmy levels ranged from 13%-100% in affected individuals (PS4; PMIDs: 11456298, 14684687, 15576045, 14705112, 16044424, 16023078, 17535832, 18078792, 19135620, 19617458, 19520270, 20691940, 20226758, 20972245, 22364517, 28429146, 27450679, 30128709, 31261379). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at 3% in blood (PMID: 11456298), however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant was seen in the mother’s blood in two other families (36% heteroplasmy in PMID: 16044424; 5% in mother’s blood and undetectable in maternal grandmother’s blood in PMID: 16023078), however no clinical details were provided on these family members to know if they were healthy or affected. There are at least six reports of de novo occurrences of this variant (PM6_strong; PMIDs: 14705112, 18078792, 19520270, 22364517, 27450679). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 14705112). 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). 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 August 23, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting, PM6_strong, PS4. -

Mitochondrial complex 1 deficiency, mitochondrial type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.89
Hmtvar	Pathogenic	0.57
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.26	T
DEOGEN2	Uncertain	0.55	D
LIST_S2	Benign	0.83	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	4.9e-14	A
PROVEAN	Uncertain	-2.5	D
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
GERP RS		1.5
Varity_R		0.62

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606890; hg19: chrM-10192;