M-10663-T-C

Variant names:

• chrM-10663-T-C
• rs1556423844
• unassigned_transcript_4810:c.194T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_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:4 O:1 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]

ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

TRNR (HGNC:7496): (mitochondrially encoded tRNA arginine)

ACMG classification

Our verdict: Pathogenic. The variant received 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
ND4	unassigned_transcript_4811	c.-97T>C		upstream_gene_variant
TRNR	unassigned_transcript_4809	c.*194T>C		downstream_gene_variant

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.

Alfa AF: 0.00 Hom.: 0

Mitomap

LHON

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:3 Other:1

Feb 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status. -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Pathogenic:1

Jun 13, 2022

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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: 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

Other links and lift over

dbSNP: rs1556423844; hg19: chrM-10664;