M-10191-T-C
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_ModeratePM2PP3PP5_Very_Strong
The ENST00000361227.2(MT-ND3):c.133T>C(p.Ser45Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Mitomap GenBank:
Absent
Consequence
MT-ND3
ENST00000361227.2 missense
ENST00000361227.2 missense
Scores
Apogee2
Pathogenic
Clinical Significance
Leigh-Disease-/-ESOC
Conservation
PhyloP100: 3.31
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 Pathogenic. Variant got 13 ACMG points.
PS1
?
Transcript ENST00000361227.2 (MT-ND3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
?
No frequency data in Mitomap. Probably very rare.
PP3
?
Apogee2 supports a deletorius effect, 0.8850099 >= 0.5 .
PP5
?
Variant M-10191-T-C is Pathogenic according to our data. Variant chrM-10191-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9712.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-ND3 | ENST00000361227.2 | c.133T>C | p.Ser45Pro | missense_variant | 1/1 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Mitomap
Leigh-Disease-/-ESOC
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Leigh syndrome Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 17, 2019 | 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 - |
Mitochondrial complex I deficiency Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Mitochondrial disease Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Aug 23, 2022 | 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 1 deficiency, mitochondrial type 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2004 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
Hmtvar
Pathogenic
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
DEOGEN2
Uncertain
D
LIST_S2
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
A
PROVEAN
Uncertain
D
Sift
Uncertain
D
Sift4G
Pathogenic
D
GERP RS
Varity_R
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at