rs199476127

Variant names:

• chrM-6721-T-C
• rs199476127
• ENST00000361624.2:c.818T>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.6721T>C (p.M273T) variant in MT-CO1 has been reported in one individual to date, in a 58-year-old woman with acquired idiopathic sideroblastic anemia (PMID:9389715). The variant was present in bone marrow from the proband and absent in her mother’s blood (PM6_supporting). There have not been additional affected individuals reported to date. 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 0.72 (Min=0, Max=1; APOGEE2 score is 0.834), 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 March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP3, PM2_supporting, PM6_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120610/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO1 ENST00000361624.2 missense
• Scores: Apogee2 Pathogenic 0.83
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 Acquired-Idiopathic-Sideroblastic-Anemia
• Conservation: PhyloP100: 4.02
• Publications: 6 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.

• 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
COX1	unassigned_transcript_4799	c.818T>C	p.Met273Thr	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO1	ENST00000361624.2	c.818T>C	p.Met273Thr	missense_variant	Exon 1 of 1	6		ENSP00000354499.2

Frequencies

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

Mitomap

Disease(s): Acquired-Idiopathic-Sideroblastic-Anemia

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Myelodysplastic syndrome with ring sideroblasts Pathogenic:1

Dec 15, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Mar 11, 2024

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.6721T>C (p.M273T) variant in MT-CO1 has been reported in one individual to date, in a 58-year-old woman with acquired idiopathic sideroblastic anemia (PMID: 9389715). The variant was present in bone marrow from the proband and absent in her mother’s blood (PM6_supporting). There have not been additional affected individuals reported to date. 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 0.72 (Min=0, Max=1; APOGEE2 score is 0.834), 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 March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP3, PM2_supporting, PM6_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.83
Hmtvar	Pathogenic	0.85
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.14	T
DEOGEN2	Benign	0.22	T
LIST_S2	Benign	0.81	T
MutationAssessor	Pathogenic	4.7	H
PhyloP100		4.0
PROVEAN	Uncertain	-4.4	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.3
Varity_R		0.66
Mutation Taster		=25/75	disease causing

Other links and lift over

dbSNP: rs199476127; hg19: chrM-6722;