ENST00000361567.2:c.1177G>A

Variant names:

• chrM-13513-G-A
• rs267606897
• ENST00000361567.2:c.1177G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS4 PP1_Moderate PM5 PP3 PM6_Strong

This summary comes from the ClinGen Evidence Repository: The m.13513G>A (p. D393N) variant in MT-ND5 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID:32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with onset typically in childhood with some reports of onset in adolescence who had features variably consistent with Leigh syndrome, MELAS and MELAS-like, and/or mitochondrial encephalopathy (PS4; PMID:25681084; PMID:27344355; PMID:30128709; PMID:12624137; PMID:14520659; PMID:17400793; PMID:18495510). This variant has been identified as a de novo occurrence in at least 5 probands with primary mitochondrial disease (PM6_strong; PMID:27344355; PMID:17400793; PMID:18495510). This variant heteroplasmy level segregated with severity in 6 families where healthy mothers were found to have the variant at low heteroplasmy levels (PP1_moderate; PMID:25681084; PMID:12624137; PMID:14520659). Another variant at this amino acid position leading to a different amino acid change is classified as pathogenic by mitomap.org and ClinVar – m.13514A>G (p.D393G; PM5). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.97 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6_strong, PM5, PP1_moderate, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA120632/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND5 ENST00000361567.2 missense
• Scores: Apogee2 Pathogenic 0.92
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:2 Leigh-Disease-/-MELAS-/-LHON-MELAS-Overlap-Syndrome-/-negative-association-w-Carotid-Atherosclerosis
• Conservation: PhyloP100: 9.29
• Publications: 42 publications found

Genes affected

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) 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; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND5 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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
ND5	unassigned_transcript_4815	c.1177G>A	p.Asp393Asn	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.1177G>A	p.Asp393Asn	missense_variant	Exon 1 of 1	6		ENSP00000354813.2

Frequencies

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

Alfa AF: 0.0000219 Hom.: 0

Mitomap

Disease(s): Leigh-Disease-/-MELAS-/-LHON-MELAS-Overlap-Syndrome-/-negative-association-w-Carotid-Atherosclerosis

Status: Cfrm-[P]

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome Pathogenic:3 Other:1

Oct 05, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.13513G>A (YP_003024036.1:p.Asp393Asn) variant in MTND5 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS3 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 22, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Pathogenic:3

Oct 26, 2021

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.13513G>A (p. D393N) variant in MT-ND5 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with onset typically in childhood with some reports of onset in adolescence who had features variably consistent with Leigh syndrome, MELAS and MELAS-like, and/or mitochondrial encephalopathy (PS4; PMID: 25681084; PMID: 27344355; PMID: 30128709; PMID: 12624137; PMID: 14520659; PMID: 17400793; PMID: 18495510). This variant has been identified as a de novo occurrence in at least 5 probands with primary mitochondrial disease (PM6_strong; PMID: 27344355; PMID: 17400793; PMID: 18495510). This variant heteroplasmy level segregated with severity in 6 families where healthy mothers were found to have the variant at low heteroplasmy levels (PP1_moderate; PMID: 25681084; PMID: 12624137; PMID: 14520659). Another variant at this amino acid position leading to a different amino acid change is classified as pathogenic by mitomap.org and ClinVar – m.13514A>G (p.D393G; PM5). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.97 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6_strong, PM5, PP1_moderate, PP3). -

Aug 04, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as heteroplasmic (40%) -

May 22, 2017

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:3

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MELAS syndrome Pathogenic:1 Other:1

Mar 01, 2008

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

- -

Leigh syndrome due to mitochondrial complex I deficiency Pathogenic:1

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.92
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.16	D
DEOGEN2	Benign	0.41	T
LIST_S2	Uncertain	0.86	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		9.3
PROVEAN	Pathogenic	-4.5	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.89

Other links and lift over

dbSNP: rs267606897; hg19: chrM-13514; COSMIC: COSV104419742; COSMIC: COSV104419742;