chrM-10158-T-C

Variant names:

• chrM-10158-T-C
• rs199476117
• ENST00000361227.2:c.100T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS4 PS3_Supporting PP3 PP1 PM2_Supporting PM6_Strong

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:6 O:1 Leigh-Disease-/-MELAS
• Conservation: PhyloP100: -2.59
• Publications: 18 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 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361227.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND3	ENST00000361227.2	TSL:6	c.100T>C	p.Ser34Pro	missense	Exon 1 of 1	ENSP00000355206.2	P03897
	MT-CO3	ENST00000362079.2	TSL:6	c.*168T>C		downstream_gene	N/A	ENSP00000354982.2	P00414
	MT-TR	ENST00000387439.1	TSL:6	n.-247T>C		upstream_gene	N/A

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

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

Status: Cfrm-[P]

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Mitochondrial complex I deficiency, mitochondrial type 1 (2)
2	-	-	not provided (2)
1	-	-	Leigh syndrome (2)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-2.6
PROVEAN	Benign	-2.1	N
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.015	D
GERP RS		-10
Varity_R		0.31

Other links and lift over

dbSNP: rs199476117; hg19: chrM-10159;