rs199476126

Positions:

• chrM-6742-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: COX1 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

Genes affected

COX1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX1	unassigned_transcript_4800	c.839T>C	p.Ile280Thr	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

Acquired-Idiopathic-Sideroblastic-Anemia

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Myelodysplastic syndrome with ring sideroblasts Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 1997

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Dec 21, 2023

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. -

Computational scores

Source: dbNSFP v4.3

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
PROVEAN	Uncertain	-3.6	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.3
Varity_R		0.80

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199476126; hg19: chrM-6743;