M-10134-C-A

Position:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2_SupportingPP4

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:1U:1
Leigh-Disease

Conservation

PhyloP100: 1.78
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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/exons MANE Protein UniProt

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MT-ND3ENST00000361227.2 linkuse as main transcriptc.76C>A p.Gln26Lys 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

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Leigh syndrome Pathogenic:1
Pathogenic, no assertion criteria providedresearchSimons Lab, The University of QueenslandMay 15, 2014Homoplasmic 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
Uncertain significance, reviewed by expert panelcurationClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGenNov 28, 2023The 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
MutationTaster
Benign
5.5e-7
A
PROVEAN
Uncertain
-3.8
D
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
GERP RS
5.1
Varity_R
0.69

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587780529; hg19: chrM-10135; API