rs199476106
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_ModeratePM1PM2PP3PP5_Very_Strong
The ENST00000361681.2(MT-ND6):c.179T>C(p.Leu60Ser) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Mitomap GenBank:
Absent
Consequence
MT-ND6
ENST00000361681.2 missense
ENST00000361681.2 missense
Scores
Apogee2
Pathogenic
Clinical Significance
LHON
Conservation
PhyloP100: 6.87
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 Pathogenic. Variant got 15 ACMG points.
PS1
?
Transcript ENST00000361681.2 (MT-ND6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
?
In a transmembrane_region Helical (size 20) in uniprot entity NU6M_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in ENST00000361681.2
PM2
?
No frequency data in Mitomap. Probably very rare.
PP3
?
Apogee2 supports a deletorius effect, 0.93043846 >= 0.5 .
PP5
?
Variant M-14495-A-G is Pathogenic according to our data. Variant chrM-14495-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9691.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-ND6 | ENST00000361681.2 | c.179T>C | p.Leu60Ser | 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
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Leber optic atrophy Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
Mitochondrial disease Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jun 30, 2022 | The m.14495A>G (p.L60S) variant in MT-ND6 has been reported in five individuals from three families, all of whom had LHON (PS4_supporting; PMIDs: 2287992, 11133798). There are no reports of de novo occurrences to our knowledge. This variant segregated with disease in one family with LHON (all testing was performed in blood; affected individuals: proband/mother with variant present at 51% heteroplasmy, sons with variant at 93% and 92%; unaffected individuals: sister with variant at 23%, maternal niece with variant at 53%, and maternal nephew with variant at 37%; PP1_moderate; PMID: 11133798). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.87 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. This variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the strong segregation evidence and consistent phenotype in affected individuals. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on April 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
Hmtvar
Pathogenic
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
DEOGEN2
Pathogenic
D
LIST_S2
Benign
T
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PROVEAN
Pathogenic
D
Sift
Uncertain
D
Sift4G
Pathogenic
D
GERP RS
Varity_R
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at