M-10663-T-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Mitomap GenBank:
Absent
Consequence
ND4L
missense
missense
Scores
Apogee2
Pathogenic
Clinical Significance
LHON
Conservation
PhyloP100: 5.84
Genes affected
ND4L (HGNC:7460): (mitochondrially encoded NADH 4L dehydrogenase) Predicted to enable NADH dehydrogenase (ubiquinone) activity. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy and diabetes mellitus. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
No frequency data in Mitomap. Probably very rare.
PP5
Variant M-10663-T-C is Pathogenic according to our data. Variant chrM-10663-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9707.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ND4L | unassigned_transcript_4810 | c.194T>C | p.Val65Ala | missense_variant | Exon 1 of 1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|
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:4Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Leber optic atrophy Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
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.10663T>C (YP_003024034.1:p.Val65Ala) variant in MTND4L gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS4 - |
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 | Feb 01, 2002 | - - |
Mitochondrial disease Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jun 13, 2022 | The m.10663 T>C (p.Val65Ala) variant in MT-ND4L has been reported in 8 different families in 28 individuals total with LHON phenotype and seen in haplogroup J and L (PS4_moderate; PMIDs: 29210930, 11935318, 24568867, 22879922, 17003408). There are 3 reported cases with no family history and assumed de novo occurrences of this variant (PM6; PMIDs: 22879922, 29210930, 11935318). This variant is not been seen in the population databases after removing known patients with mitochondrial disease > 0.002% (PM2_supporting). In silico tools (APOGEE) is 0.9 which predicts this variant to be pathogenic (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 11935318). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on June 13 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4_moderate, PM2_supporting, PM6, PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
Hmtvar
Pathogenic
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
DEOGEN2
Benign
T
LIST_S2
Benign
T
PROVEAN
Uncertain
D
Sift
Uncertain
D
Sift4G
Benign
T
GERP RS
Varity_R
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at