ENST00000361624.2:c.425C>T

Variant names:

• chrM-6328-C-T
• rs267606883
• ENST00000361624.2:c.425C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.6328C>T (p.S142F) variant in MT-CO1 has been reported in one individual to date with primary mitochondrial disease. This individual had a severe cardioencephalomyopathy resembling mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and harbored the variant at >95% heteroplasmy in muscle (PMID:16284789). P. denitrificans models support a deleterious functional impact of this variant (PS3_supporting; PMID:16284789). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic and each had a raw score of 0.90 (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). 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 December 21, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS3_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120615/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO1 ENST00000361624.2 missense
• Scores: Apogee2 Pathogenic 0.90
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 EXIT-(Exercise-Intolerance)
• Conservation: PhyloP100: 7.55
• Publications: 3 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: Uncertain_significance. The variant received 3 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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
COX1	unassigned_transcript_4799	c.425C>T	p.Ser142Phe	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO1	ENST00000361624.2	c.425C>T	p.Ser142Phe	missense_variant	Exon 1 of 1	6		ENSP00000354499.2

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): EXIT-(Exercise-Intolerance)

Status: Reported-[VUS]

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Cytochrome c oxidase I deficiency Pathogenic:1

Mar 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Dec 21, 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.6328C>T (p.S142F) variant in MT-CO1 has been reported in one individual to date with primary mitochondrial disease. This individual had a severe cardioencephalomyopathy resembling mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and harbored the variant at >95% heteroplasmy in muscle (PMID: 16284789). P. denitrificans models support a deleterious functional impact of this variant (PS3_supporting; PMID: 16284789). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic and each had a raw score of 0.90 (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). 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 December 21, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.90
Hmtvar	Pathogenic	0.86
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.12	D
DEOGEN2	Benign	0.18	T
LIST_S2	Uncertain	0.92	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		7.6
PROVEAN	Pathogenic	-4.7	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.3
Varity_R		0.86
Mutation Taster		=57/43	polymorphism

Other links and lift over

dbSNP: rs267606883; hg19: chrM-6329;