chrM-14597-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5
The ENST00000361681.2(MT-ND6):c.77T>C(p.Ile26Thr) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I26M) has been classified as Likely pathogenic.
Frequency
Mitomap GenBank:
Absent
Consequence
MT-ND6
ENST00000361681.2 missense
ENST00000361681.2 missense
Scores
Apogee2
Pathogenic
Clinical Significance
LHON-/-LS
Conservation
PhyloP100: 1.68
Genes affected
MT-ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
No frequency data in Mitomap. Probably very rare.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
?
Apogee2 supports a deletorius effect, 0.6300216 >= 0.5 .
PP5
?
Variant M-14597-A-G is Pathogenic according to our data. Variant chrM-14597-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 209173.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-ND6 | ENST00000361681.2 | c.77T>C | p.Ile26Thr | 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
LHON-/-LS
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Dysarthria;C0013421:Dystonic disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2014 | Likely pathogenicity based on finding it once in our laboratory de novo and 49% heteroplasmic in a 31-year-old male with profound and progressive generalized dystonia, dysarthria, prominent perivascular spaces. This same codon was affected in a family with Leber optic atrophy and hereditary spastic dystonia (PMID 8644732). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Leigh syndrome Uncertain:1
Uncertain significance, 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.14597A>G (YP_003024037.1:p.Ile26Thr) variant in MTND6 gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PM9, PP6, PP7 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
Hmtvar
Pathogenic
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
DEOGEN2
Uncertain
D
LIST_S2
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PROVEAN
Pathogenic
D
Sift
Pathogenic
D
Sift4G
Uncertain
D
GERP RS
Varity_R
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at