rs267606896

Positions:

• chrM-13084-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ND5 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

Genes affected

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ND5	unassigned_transcript_4815	c.748A>T	p.Ser250Cys	missense_variant	1/1

Ensembl

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

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

MELAS-/-Leigh-Disease

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 10, 2003	- -

Leigh syndrome due to mitochondrial complex I deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 10, 2003

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Nov 13, 2023

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. -

Computational scores

Source: dbNSFP v4.3

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
PROVEAN	Pathogenic	-4.5	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.94

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606896; hg19: chrM-13085;