ENST00000361789.2:c.404G>A

Variant names:

• chrM-15150-G-A
• rs207460000
• ENST00000361789.2:c.404G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120619/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-CYB ENST00000361789.2 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 EXIT
• Conservation: PhyloP100: 9.24
• Publications: 5 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: Likely_pathogenic. The variant received 5 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

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

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CYB	ENST00000361789.2	TSL:6	c.404G>A	p.Trp135*	stop_gained	Exon 1 of 1	ENSP00000354554.2

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Alfa AF: 0.00331 Hom.: 86

Mitomap

Disease(s): EXIT

Status: Cfrm-[LP]

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Exercise intolerance (1)
1	-	-	Leber optic atrophy (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Mitochondrial myopathy with reversible cytochrome C oxidase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

Other links and lift over

dbSNP: rs207460000; hg19: chrM-15151;