M-15615-G-A

Variant names:

• chrM-15615-G-A
• rs207459997
• ENST00000361789.2:c.869G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The ENST00000361789.2(MT-CYB):​c.869G>A​(p.Gly290Asp) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 4/4 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G290S) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CYB ENST00000361789.2 missense
• Scores: Apogee2 Pathogenic 0.97
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 EXIT-/-Antimycin-resistance
• Conservation: PhyloP100: 9.28
• Publications: 10 publications found

Genes affected

MT-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CYB Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex III deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.97373956 >= 0.5 .
• PP5: Variant M-15615-G-A is Pathogenic according to our data. Variant chrM-15615-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 9678.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361789.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CYB	ENST00000361789.2	TSL:6	c.869G>A	p.Gly290Asp	missense	Exon 1 of 1	ENSP00000354554.2

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): EXIT-/-Antimycin-resistance

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial myopathy with reversible cytochrome C oxidase deficiency Pathogenic:1

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.15615G>A (YP_003024038.1:p.Gly290Asp) variant in MTCYB gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PM8, PM10, PP6, PP7

Exercise intolerance Pathogenic:1

Sep 30, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mitochondrial disease Uncertain:1

Feb 04, 2025

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.15615G>A (p.Gly290Asp) variant in MT-CYB has been reported in one individual with primary mitochondrial disease (PMID: 8910895). This individual had exercise intolerance, elevated blood lactate, and ragged red fibers on muscle biopsy. Complex III deficiency was noted in muscle. The variant was present at 80% heteroplasmy in muscle and was undetectable in blood. The variant was also undetectable in blood from the unaffected mother and two unaffected sisters. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE1 gives a consensus rating of pathogenic with a score of 0.82 (Min=0, Max=1, PP3). There are no single fiber studies or other functional assays reported for 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 February 4, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.97
Hmtvar	Pathogenic	0.86
AlphaMissense	Pathogenic	0.94
PhyloP100		9.3

Other links and lift over

dbSNP: rs207459997; hg19: chrM-15616; COSMIC: COSV107464488; COSMIC: COSV107464488;