rs207460002

Positions:

• chrM-15579-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP5_Strong

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: CYTB missense
• Scores: Apogee2 Pathogenic 0.92
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:1 Multisystem-Disorder+-EXIT
• Conservation: PhyloP100: 8.66

Genes affected

CYTB (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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-15579-A-G is Pathogenic according to our data. Variant chrM-15579-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 9683.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYTB	unassigned_transcript_4818	c.833A>G	p.Tyr278Cys	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

Multisystem-Disorder+-EXIT

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial myopathy with reversible cytochrome C oxidase deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Oct 17, 2019

The NC_012920.1:m.15579A>G (YP_003024038.1:p.Tyr278Cys) variant in MTCYB gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished).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, PM9, PM10, PP4, PP6 -

Leber optic atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Multisystem disorder Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2001

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Jul 11, 2022

The m.15579A>G (p.Y278C) variant in MT-CYB has been reported in one individual with primary mitochondrial disease. This woman had exercise intolerance, epilepsy, intellectual disability, hearing loss, retinal dystrophy, and cataracts (PMID: 11601507). The variant was heteroplasmic in muscle (88%) and leucocytes (15%). The variant was reported as de novo as it was absent in mother’s blood, however no additional tissues were tested and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. 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 0.78 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). A dramatic reduction of Complex III activity and Complex III-driven ATP synthesis, enhanced superoxide production, and a perturbation of glutathione homeostasis were seen in a cybrid homoplasmic for this variant (PMID: 23418307; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt likely pathogenic or pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214); PM2_supporting, PP3, PS3_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.92
Hmtvar	Pathogenic	0.88
AlphaMissense	Pathogenic	0.86

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs207460002; hg19: chrM-15580;