rs267606891

Variant names:

• chrM-10197-G-A
• rs267606891
• ENST00000361227.2:c.139G>A

Your query was ambiguous. Multiple possible variants found:

• chrM-10197-G-A
• chrM-10197-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM6 PS4 PP1_Moderate PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120640/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:11 O:1 Leigh-Disease-/-Dystonia-/-Stroke-/-LDYT,Leigh-Disease
• Conservation: PhyloP100: 4.69
• Publications: 21 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.
• 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.139G>A	p.Ala47Thr	missense	Exon 1 of 1	ENSP00000355206.2	P03897
	MT-CO3	ENST00000362079.2	TSL:6	c.*207G>A		downstream_gene	N/A	ENSP00000354982.2	P00414
	MT-TR	ENST00000387439.1	TSL:6	n.-208G>A		upstream_gene	N/A

Frequencies

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

Alfa AF: 0.0000898 Hom.: 0

Mitomap

Disease(s): Leigh-Disease-/-Dystonia-/-Stroke-/-LDYT,Leigh-Disease

Status: Cfrm-[P],Reported

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Leigh syndrome (3)
2	-	-	Mitochondrial complex I deficiency, mitochondrial type 1 (2)
1	-	-	Leber optic atrophy and dystonia (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Mitochondrial DNA-Associated Leigh Syndrome and NARP (1)
1	-	-	Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy (1)
1	-	-	not provided (1)
1	-	-	not specified (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.7
PROVEAN	Uncertain	-3.5	D
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.1
Varity_R		0.22
Mutation Taster		=38/62	disease causing

Other links and lift over

dbSNP: rs267606891; hg19: chrM-10198; COSMIC: COSV107450097; COSMIC: COSV107450097;