rs28679680

Variant names:

• chrM-6930-G-A
• rs28679680
• ENST00000361624.2:c.1027G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM6_Supporting PVS1_Strong PS3_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.6930G>A (p.G343Ter) variant in MT-CO1 has been reported in one individual to date, in a woman with a multisystem disorder (PMID:10441567). Clinical features included cataracts, profound sensorineural hearing loss, myoclonic epilepsy, cerebellar ataxia, progressive muscle weakness and atrophy, progressive vision loss due to optic atrophy, and a severe sensorimotor neuropathy. Brain imaging showed diffuse cerebellar atrophy and bilateral small symmetrical nodular hyperintensities in the basal ganglia (head of the caudatus and putamen). She had elevated blood lactate (5.8 mM, normal 0.1-2.2) and CK (1000 UI/L; normal <150). Muscle biopsy showed that only 10% of fibers showed normal COX staining and her complex IV activity was 10% of controls. The variant was present at 27% heteroplasmy in blood, 75% in muscle, and 33% in myoblasts. As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood from her mother, sister, and four maternal aunts (PM6_supporting). Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). This variant results in loss of the last 170 amino acids (33% of the protein, PVS1_strong). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 10441567, 11595737). In summary, this variant meets criteria to be classified as likely pathogenic 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 January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM6_supporting, PM2_supporting, PS3_supporting, PVS1_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120612/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO1 ENST00000361624.2 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 Multisystem-Disorder
• Conservation: PhyloP100: 9.54
• Publications: 5 publications found

Genes affected

MT-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial non-syndromic sensorineural hearing loss

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX1	unassigned_transcript_4799	c.1027G>A	p.Gly343*	stop_gained	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO1	ENST00000361624.2	c.1027G>A	p.Gly343*	stop_gained	Exon 1 of 1	6		ENSP00000354499.2

Frequencies

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

Alfa AF: 0.0000273 Hom.: 0

Mitomap

Disease(s): Multisystem-Disorder

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Sep 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Jan 22, 2024

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.6930G>A (p.G343Ter) variant in MT-CO1 has been reported in one individual to date, in a woman with a multisystem disorder (PMID: 10441567). Clinical features included cataracts, profound sensorineural hearing loss, myoclonic epilepsy, cerebellar ataxia, progressive muscle weakness and atrophy, progressive vision loss due to optic atrophy, and a severe sensorimotor neuropathy. Brain imaging showed diffuse cerebellar atrophy and bilateral small symmetrical nodular hyperintensities in the basal ganglia (head of the caudatus and putamen). She had elevated blood lactate (5.8 mM, normal 0.1-2.2) and CK (1000 UI/L; normal <150). Muscle biopsy showed that only 10% of fibers showed normal COX staining and her complex IV activity was 10% of controls. The variant was present at 27% heteroplasmy in blood, 75% in muscle, and 33% in myoblasts. As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood from her mother, sister, and four maternal aunts (PM6_supporting). Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). This variant results in loss of the last 170 amino acids (33% of the protein, PVS1_strong). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 10441567, 11595737). In summary, this variant meets criteria to be classified as likely pathogenic 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 January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PS3_supporting, PVS1_strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.69	D
DEOGEN2	Uncertain	0.45	T
LIST_S2	Pathogenic	0.98	D
MutationAssessor	Pathogenic	5.6	H
PhyloP100		9.5
PROVEAN	Pathogenic	-5.0	D
GERP RS		5.0
Varity_R		0.88
Mutation Taster		=8/92	disease causing

Other links and lift over

dbSNP: rs28679680; hg19: chrM-6931;