rs207459999

Variant names:

• chrM-15242-G-A
• rs207459999
• ENST00000361789.2:c.496G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PS3_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.15242G>A (p.Gly166Ter) variant in MT-CYB has been reported in one individual with primary mitochondrial disease. This individual had exercise intolerance, lactic acidosis, encephalomyopathy, hallucinations, depression, memory loss, and seizures. The variant was present at 87-92% heteroplasmy in muscle, 0.7% in blood, and 4-14% in hair roots (PMID:11047755). This variant was also seen in her unaffected sister (<0.2% in blood) and was undetectable in blood from her healthy mother, however this cannot be considered evidence for segregation nor de novo occurrence as the variant was detected at very low levels in the proband’s blood. This variant causes a premature stop in the MT-CYB gene (PVS1_strong). 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. Single fiber testing showed higher levels of the variant in ragged red fibers (89±8%) than in non-ragged red fibers (66±26%) p<0.0001 (PS3_supporting, PMID:11047755). In summary, this variant meets criteria to be classified as likely pathogenic 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 January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PVS1_strong, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120618/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CYB ENST00000361789.2 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 Mitochondrial-Encephalomyopathy
• Conservation: PhyloP100: 7.44
• Publications: 3 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 6 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTB	unassigned_transcript_4818	c.496G>A	p.Gly166*	stop_gained	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CYB	ENST00000361789.2	c.496G>A	p.Gly166*	stop_gained	Exon 1 of 1	6		ENSP00000354554.2

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Mitochondrial-Encephalomyopathy

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome 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.15242G>A (YP_003024038.1:p.Gly166Ter) 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: PS3, PS6, PM8, PM9 -

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.15242G>A (p.Gly166Ter) variant in MT-CYB has been reported in one individual with primary mitochondrial disease. This individual had exercise intolerance, lactic acidosis, encephalomyopathy, hallucinations, depression, memory loss, and seizures. The variant was present at 87-92% heteroplasmy in muscle, 0.7% in blood, and 4-14% in hair roots (PMID:11047755). This variant was also seen in her unaffected sister (<0.2% in blood) and was undetectable in blood from her healthy mother, however this cannot be considered evidence for segregation nor de novo occurrence as the variant was detected at very low levels in the proband’s blood. This variant causes a premature stop in the MT-CYB gene (PVS1_strong). 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. Single fiber testing showed higher levels of the variant in ragged red fibers (89±8%) than in non-ragged red fibers (66±26%) p<0.0001 (PS3_supporting, PMID: 11047755). In summary, this variant meets criteria to be classified as likely pathogenic 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 January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PVS1_strong, PS3_supporting. -

Mitochondrial encephalomyopathy Pathogenic:1

Dec 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=41/59	disease causing

Other links and lift over

dbSNP: rs207459999; hg19: chrM-15243; COSMIC: COSV62378067; COSMIC: COSV62378067;