chrM-13045-A-C

Variant names:

• chrM-13045-A-C
• rs267606895
• ENST00000361567.2:c.709A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM6_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120629/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND5 ENST00000361567.2 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
• Publications: 21 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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.709A>C	p.Met237Leu	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.709A>C	p.Met237Leu	missense_variant	Exon 1 of 1	6		ENSP00000354813.2

Frequencies

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

Mitomap

Disease(s): MELAS-/-LHON-/-Leigh-overlap-syndrome,MELAS

Status: Reported-[VUS],Reported

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

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

MELAS syndrome Pathogenic:1

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leber optic atrophy Pathogenic:1

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Nov 13, 2023

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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
PhyloP100		6.9
GERP RS		3.2
Varity_R		0.83
Mutation Taster		=52/48	disease causing (ClinVar)

Other links and lift over

dbSNP: rs267606895; hg19: chrM-13046;