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

Scores

Apogee2
Pathogenic
0.82

Clinical Significance

Likely pathogenic reviewed by expert panel P:4O:1
LHON

Conservation

PhyloP100: 5.84
Variant links:
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
ND4Lunassigned_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
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 submitterclinical testingMendelicsMay 04, 2022- -
Pathogenic, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineOct 17, 2019The 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variant in MTND4L gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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 providedliterature onlyGeneReviews-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 providedliterature onlyOMIMFeb 01, 2002- -
Mitochondrial disease Pathogenic:1
Likely pathogenic, reviewed by expert panelcurationClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGenJun 13, 2022The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
0.82
Hmtvar
Pathogenic
0.58
AlphaMissense
Uncertain
0.48
BayesDel_addAF
Benign
-0.22
T
DEOGEN2
Benign
0.10
T
LIST_S2
Benign
0.65
T
PROVEAN
Uncertain
-4.0
D
Sift
Uncertain
0.0090
D
Sift4G
Benign
0.78
T
GERP RS
5.1
Varity_R
0.38

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: rs1556423844; hg19: chrM-10664; API