m.13513G>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:12 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361567.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND5	ENST00000361567.2	TSL:6	c.1177G>A	p.Asp393Asn	missense	Exon 1 of 1	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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Leigh syndrome (4)
3	-	-	Mitochondrial disease (3)
3	-	-	not provided (3)
2	-	-	MELAS syndrome (3)
1	-	-	Leigh syndrome due to mitochondrial complex I deficiency (1)

Computational scores

Source: dbNSFP v4.9

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;