rs1556423844

Variant names:

• chrM-10663-T-C
• rs1556423844
• ENST00000361335.1:c.194T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PS4_Moderate PS3_Supporting PP3 PM2_Supporting

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
• Publications: 0 publications found

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]

MT-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)

TRNR Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 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
MT-ND4L	ENST00000361335.1	c.194T>C	p.Val65Ala	missense_variant	Exon 1 of 1	6		ENSP00000354728.1
MT-ND4	ENST00000361381.2	c.-97T>C		upstream_gene_variant		6		ENSP00000354961.2
MT-TR	ENST00000387439.1	n.*194T>C		downstream_gene_variant		6

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): LHON

Status: Cfrm-[LP]

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

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 -

Feb 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

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
PhyloP100		5.8
PROVEAN	Uncertain	-4.0	D
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.78	T
GERP RS		5.1
Varity_R		0.38

Other links and lift over

dbSNP: rs1556423844; hg19: chrM-10664;