rs267606890

Variant names:

• chrM-10191-T-C
• rs267606890
• ENST00000361227.2:c.133T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS4 PS3_Supporting PP3 PM2_Supporting PM6_Strong

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
• Publications: 20 publications found

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]

MT-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

TRNR (HGNC:7496): (mitochondrially encoded tRNA arginine)

TRNG (HGNC:7486): (mitochondrially encoded tRNA glycine)

TRNG Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
ND3	unassigned_transcript_4808	c.133T>C	p.Ser45Pro	missense_variant	Exon 1 of 1
TRNR	unassigned_transcript_4809	c.-214T>C		upstream_gene_variant
COX3	unassigned_transcript_4806	c.*201T>C		downstream_gene_variant
TRNG	unassigned_transcript_4807	c.*133T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND3	ENST00000361227.2	c.133T>C	p.Ser45Pro	missense_variant	Exon 1 of 1	6		ENSP00000355206.2
MT-CO3	ENST00000362079.2	c.*201T>C		downstream_gene_variant		6		ENSP00000354982.2
MT-TR	ENST00000387439.1	n.-214T>C		upstream_gene_variant		6
MT-TG	ENST00000387429.1	n.*133T>C		downstream_gene_variant		6

Frequencies

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

Alfa AF: 0.0000544 Hom.: 1

Mitomap

Disease(s): Leigh-Disease-/-ESOC

Status: Cfrm-[P]

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome Pathogenic:1 Other:1

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.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 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mitochondrial complex I deficiency Pathogenic:1

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mitochondrial disease Pathogenic:1

Aug 23, 2022

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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 I deficiency, mitochondrial type 1 Pathogenic:1

Jan 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		3.3
PROVEAN	Uncertain	-2.5	D
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
GERP RS		1.5
Varity_R		0.62

Other links and lift over

dbSNP: rs267606890; hg19: chrM-10192;