M-10663-T-C

Position:

• chrM-10663-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 5 ACMG points: 5P and 0B. PM2_Supporting PS4_Moderate PS3_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The m.10663T>C (p.V65A) variant in MT-ND4L has been reported in at least 28 individuals from eight families, all of whom had Leber Hereditary Optic Neuropathy (LHON) and were haplogroup J and L (PS4_moderate; PMIDs: 29210930, 11935318, 24568867, 22879922, 17003408). There are three reported cases with no family history and, while these variants were assumed to occur de novo, family members were not tested for the variant. Several extended families have been reported in the medical literature (PMID:24568867) however the variant was homoplasmic and thus prevented consideration for PP1. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are several occurrences in population databases, however some of these are from reported affected individuals (two occurrences in the GenBank dataset however one is from a patient with known mitochondrial disease, one occurrence in the Helix dataset, absent in gnomAD). Although there are several occurrences, the frequency is still low (PM2_supporting). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID:11935318). This variant meets criteria to be classified as uncertain significance however this Expert Panel elected to modify the classification to likely pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common variants associated with LHON. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS3_supporting, PS4_moderate, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340938/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND4L ENST00000361335.1 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

MT-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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 5 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ND4L	ENST00000361335.1	c.194T>C	p.Val65Ala	missense_variant	1/1			ENSP00000354728	P1

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:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2002	- -
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, 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 -

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: 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
MutationTaster	Benign	0.12	A
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;