rs267606896

Variant names:

• chrM-13084-A-T
• rs267606896
• ENST00000361567.2:c.748A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP1 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.13084A>T (p.S250C) variant in MT-ND5 has been reported in one family with primary mitochondrial disease to date (PMIDs: 12509858, 33062892). The proband was a boy with features and brain imaging findings consistent with both Leigh syndromes spectrum disorder and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) including neurodegeneration, stroke-like episodes, seizures, myoclonic jerks, bradykinesia, ataxia, dysarthria, decreased visual acuity, ptosis, hearing loss, and right bundle branch block. Complex I activity was mildly reduced in muscle. The variant was present at 85% in muscle, 82% in blood, 99% in buccal cells, 67% in urine, and 72% in fibroblast cell line. The proband’s mother was more mildly affected with migraines and Leber Hereditary Optic Neuropathy (LHON). The variant was present at 75% in lymphocytes and 48% in fibroblasts. The proband’s sister had brisk reflexes and diffuse slow wave activity on electroencephalogram (EEG) and had the variant present at 41% in lymphocytes and 13% in fibroblasts (PP1). There are no additional individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.61 (Min=0, Max=1; APOGEE2 score is 0.883), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP1, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120631/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND5 ENST00000361567.2 missense
• Scores: Apogee2 Pathogenic 0.88
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 O:1 MELAS-/-Leigh-Disease
• Conservation: PhyloP100: 6.87
• Publications: 2 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: G2P, Orphanet
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: 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.748A>T	p.Ser250Cys	missense	Exon 1 of 1	ENSP00000354813.2	P03915

Frequencies

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

Mitomap

Disease(s): MELAS-/-Leigh-Disease

Status: Reported-[VUS]

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Leigh syndrome due to mitochondrial complex I deficiency (1)
1	-	-	MELAS syndrome (2)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.88
Hmtvar	Pathogenic	0.82
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.048	T
DEOGEN2	Benign	0.34	T
LIST_S2	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.9
PROVEAN	Pathogenic	-4.5	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.94
Mutation Taster		=53/47	polymorphism

Other links and lift over

dbSNP: rs267606896; hg19: chrM-13085;