rs281865417

Variant names:

• chrM-6277-G-A
• rs281865417
• ENST00000361624.2:c.374G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The ENST00000361624.2(MT-CO1):​c.374G>A​(p.Gly125Asp) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 7/11 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G125G) has been classified as Likely benign.

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO1 ENST00000361624.2 missense
• Scores: Apogee2 Pathogenic 0.79
• Clinical Significance: Pathogenic no assertion criteria provided P:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 9.46
• Publications: 7 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 4 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.7946888 >= 0.5 .
• PP5: Variant M-6277-G-A is Pathogenic according to our data. Variant chrM-6277-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 9672.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX1	unassigned_transcript_4799	c.374G>A	p.Gly125Asp	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO1	ENST00000361624.2	c.374G>A	p.Gly125Asp	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

No disease associated.

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial colorectal cancer Pathogenic:1

Mar 03, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.79
Hmtvar	Pathogenic	0.88
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.027	T
DEOGEN2	Uncertain	0.50	T
LIST_S2	Uncertain	0.97	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		9.5
PROVEAN	Pathogenic	-5.8	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.3
Varity_R		0.85

Other links and lift over

dbSNP: rs281865417; hg19: chrM-6278;