rs587780529

Variant names:

• chrM-10134-C-A
• rs587780529
• ENST00000361227.2:c.76C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.10134C>A (p.Q26K) variant in MT-ND3 has been reported in one individual to date, in a girl with Leigh syndrome spectrum disorder (PMID:25118196). She was reportedly slower than her siblings in reaching motor milestones and at 4-years-old lost the ability to jump, developed an abnormal gait, and had speech difficulty. At 4.5-years-old, she developed worsening speech, mobility, balance, and behaviors after undergoing anesthesia. Brain MRI performed at this time showed extensive signal abnormality involving putamen, globus pallidus bilaterally, and the cerebral peduncles, and brain MRS showed elevated lactate in the basal ganglia. Blood and cerebrospinal fluid (CSF) lactates were normal. Muscle biopsy showed fat accumulation and slightly increased subsarcolemmal mitochondrial aggregates. Liver biopsy showed increased glycogen content and mild biliary ductular proliferation, and electron microscopy showed occasional moderately enlarged mitochondria with paracrystalline and crystalline inclusions. The variant was present at homoplasmy in blood, fibroblasts, liver, and muscle. As this is the only case reported to date, PS4 could not be applied. Complex I deficiency was noted in muscle, and exome sequencing was performed in the proband, her parents, and three healthy siblings ruling out other known genetic etiologies (PMID:25118196; PP4). This variant segregated with disease features in this family as her healthy mother had the variant present 1% in blood, however this does not meet criteria to apply PP1_supporting (at least two segregations). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.19 (Min=0, Max=1), which predicts no damaging effect on gene function, however an updated version of this predictor (APOGEE2) predicts a deleterious effect with a score of 0.752. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA270779/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND3 ENST00000361227.2 missense
• Scores: Apogee2 Pathogenic 0.75
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 Leigh-Disease
• Conservation: PhyloP100: 1.78
• Publications: 2 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]

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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.76C>A	p.Gln26Lys	missense_variant	Exon 1 of 1
COX3	unassigned_transcript_4806	c.*144C>A		downstream_gene_variant
TRNG	unassigned_transcript_4807	c.*76C>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND3	ENST00000361227.2	c.76C>A	p.Gln26Lys	missense_variant	Exon 1 of 1	6		ENSP00000355206.2
MT-CO3	ENST00000362079.2	c.*144C>A		downstream_gene_variant		6		ENSP00000354982.2
MT-TG	ENST00000387429.1	n.*76C>A		downstream_gene_variant		6

Frequencies

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

Mitomap

Disease(s): Leigh-Disease

Status: Reported-[VUS]

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome Pathogenic:1

May 15, 2014

Simons Lab, The University of Queensland

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Homoplasmic varient identified in single case of Leigh Syndrome resulting from mitochondrial complex I deficiency. Unaffected mother of proband was 1% heteroplasmic carrier of this varient. -

Mitochondrial disease Uncertain:1

Nov 28, 2023

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.10134C>A (p.Q26K) variant in MT-ND3 has been reported in one individual to date, in a girl with Leigh syndrome spectrum disorder (PMID: 25118196). She was reportedly slower than her siblings in reaching motor milestones and at 4-years-old lost the ability to jump, developed an abnormal gait, and had speech difficulty. At 4.5-years-old, she developed worsening speech, mobility, balance, and behaviors after undergoing anesthesia. Brain MRI performed at this time showed extensive signal abnormality involving putamen, globus pallidus bilaterally, and the cerebral peduncles, and brain MRS showed elevated lactate in the basal ganglia. Blood and cerebrospinal fluid (CSF) lactates were normal. Muscle biopsy showed fat accumulation and slightly increased subsarcolemmal mitochondrial aggregates. Liver biopsy showed increased glycogen content and mild biliary ductular proliferation, and electron microscopy showed occasional moderately enlarged mitochondria with paracrystalline and crystalline inclusions. The variant was present at homoplasmy in blood, fibroblasts, liver, and muscle. As this is the only case reported to date, PS4 could not be applied. Complex I deficiency was noted in muscle, and exome sequencing was performed in the proband, her parents, and three healthy siblings ruling out other known genetic etiologies (PMID: 25118196; PP4). This variant segregated with disease features in this family as her healthy mother had the variant present 1% in blood, however this does not meet criteria to apply PP1_supporting (at least two segregations). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.19 (Min=0, Max=1), which predicts no damaging effect on gene function, however an updated version of this predictor (APOGEE2) predicts a deleterious effect with a score of 0.752. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.75
Hmtvar	Pathogenic	0.51
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
DEOGEN2	Uncertain	0.49	T
LIST_S2	Uncertain	0.87	D
MutationAssessor	Benign	0.17	N
PhyloP100		1.8
PROVEAN	Uncertain	-3.8	D
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
GERP RS		5.1
Varity_R		0.69

Other links and lift over

dbSNP: rs587780529; hg19: chrM-10135;