rs267606895

Positions:

• chrM-13045-A-C

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 0.90
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:1 MELAS-/-LHON-/-Leigh-overlap-syndrome,MELAS
• 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.709A>C	p.Ile237Leu	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-/-LHON-/-Leigh-overlap-syndrome,MELAS

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome due to mitochondrial complex I deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2003

- -

MELAS syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2003

- -

Leber optic atrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 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.13045A>C (p.M237L) variant in MT-ND5 has been reported in one individual with primary mitochondrial disease to date (PMID: 12509858), in a boy with migraine-like symptoms (dizziness, vomiting, photophobia), clonic seizures that developed into epilepsia partialis continua, bilateral optic atrophy, ophthalmoplegia, ataxia, and cognitive impairment. He also had elevated cerebrospinal fluid lactate (normal lactate in blood) and muscle biopsy showed mildly reduced complex I activity. His brain imaging findings were consistent with Leigh syndrome and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). The variant was present at 82% heteroplasmy in muscle and 13% in blood. The variant was absent in blood from his healthy mother (PM6_supporting). There are several occurrences in population databases (absent in gnomAD v3.1.2 and the Helix dataset; present in one individual in the MITOMAP GenBank sequences, 1/61168, 0.00163%). Although there are several occurrences, the frequency is still low (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.73 (Min=0, Max=1; score of 0.905 in APOGEE2), which predicts a damaging effect on gene function (PP3). There are no cybrids, supporting single fiber studies, or de novo occurrences reported for 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): PM2_supporting, PM6_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.90
Hmtvar	Pathogenic	0.69
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.073	T
GERP RS		3.2
Varity_R		0.83

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606895; hg19: chrM-13046;