rs207459999

Variant names:

• chrM-15242-G-A
• rs207459999
• unassigned_transcript_4818:c.496G>A

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: Absent
• Consequence: CYTB missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 Mitochondrial-Encephalomyopathy
• Conservation: PhyloP100: 7.44

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: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-15242-G-A is Pathogenic according to our data. Variant chrM-15242-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9680.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.496G>A	p.Gly166Arg	missense_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

Mitochondrial-Encephalomyopathy

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variant in MTCYB gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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

Splicing

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

Publications

LitVar

Other links and lift over

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