rs207460000

Variant names:

• chrM-15150-G-A
• rs207460000
• unassigned_transcript_4818:c.404G>A

Your query was ambiguous. Multiple possible variants found:

• chrM-15150-G-A
• chrM-15150-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: CYTB stop_retained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 EXIT
• Conservation: PhyloP100: 9.24

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP5: Variant M-15150-G-A is Pathogenic according to our data. Variant chrM-15150-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9681.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTB	unassigned_transcript_4818	c.404G>A	p.Ter135Ter	stop_retained_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	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

Alfa AF: 0.00272 Hom.: 42

Mitomap

EXIT

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Jan 08, 2024

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.15150G>A (p.W135Ter) variant in MT-CYB has been reported in one individual to date, in an individual with exercise intolerance from childhood (PMID: 11464242). The variant was present at 60% heteroplasmy in skeletal muscle and was undetectable in blood and skin fibroblasts. Complex III activity was reduced in muscle and normal in leukocytes and skin fibroblasts. The variant was undetectable in blood from the healthy mother, however the significance of this is unclear given the variant was also undetectable in blood from the proband. There are no additional individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. This variant results in a significant truncation (65%) of the MT-CYB protein (PVS1_strong). 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 however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent biochemical phenotype and likely deleterious nature of this truncating variant. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting. -

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: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.15150G>A (YP_003024038.1:p.Trp135Ter) variant in MTCYB gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS6, PM8, PM9, PM10 -

Exercise intolerance Pathogenic:1

Jul 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leber optic atrophy Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs207460000; hg19: chrM-15151;