rs199476126

Variant names:

• chrM-6742-T-C
• rs199476126
• ENST00000361624.2:c.839T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.6742T>C (p.I280T) variant in MT-CO1 has been reported in one individual to date, in a man with sideroblastic anemia (PMID:9389715). The variant was present at 52% in bone marrow, 59% in peripheral blood, 71% in platelets, and was undetectable in buccal and fibroblasts. As this is the only case reported to date, PS4 could not be applied. There was no mention of family member testing precluding consideration for de novo status or segregation. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.63 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset and gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (0.001%, haplogroup I; PM2_supporting). 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 December 21, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120608/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-CO1 ENST00000361624.2 missense
• Scores: Apogee2 Uncertain 0.54
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2 Acquired-Idiopathic-Sideroblastic-Anemia
• Conservation: PhyloP100: 6.01
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361624.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CO1	ENST00000361624.2	TSL:6	c.839T>C	p.Ile280Thr	missense	Exon 1 of 1	ENSP00000354499.2	P00395

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

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

Status: Reported-[VUS]

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial disease (1)
1	-	-	Myelodysplastic syndrome with ring sideroblasts (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.54
Hmtvar	Pathogenic	0.79
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.040	T
DEOGEN2	Benign	0.26	T
LIST_S2	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		6.0
PROVEAN	Uncertain	-3.6	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.3
Varity_R		0.80

Other links and lift over

dbSNP: rs199476126; hg19: chrM-6743;