rs207459998
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The ENST00000361789.2(MT-CYB):c.100G>A(p.Gly34Ser) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.
Frequency
Mitomap GenBank:
Absent
Consequence
MT-CYB
ENST00000361789.2 missense
ENST00000361789.2 missense
Scores
Apogee2
Pathogenic
Clinical Significance
EXIT-/-possibly-antiatherogenic+-poss.-myocardial-infarction-association
Conservation
PhyloP100: 6.21
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
?
No frequency data in Mitomap. Probably very rare.
PP3
?
Apogee2 supports a deletorius effect, 0.8945994 >= 0.5 .
PP5
?
Variant M-14846-G-A is Pathogenic according to our data. Variant chrM-14846-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYTB | CYTB.1 use as main transcript | c.100G>A | p.Gly34Ser | missense_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-CYB | ENST00000361789.2 | c.100G>A | p.Gly34Ser | missense_variant | 1/1 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Mitomap
EXIT-/-possibly-antiatherogenic+-poss.-myocardial-infarction-association
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mitochondrial myopathy with reversible cytochrome C oxidase deficiency Pathogenic:1
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.14846G>A (YP_003024038.1:p.Gly34Ser) 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, PM8, PM9, PP4, PP6 - |
MT-CYB associated Exercise intolerance;na:MT-CYB associated Mitochondrial myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jul 23, 2021 | The apparently de novo m.14846G>A variant substitutes a very well conserved Guanine for Adenine at position 14846 of the mitochondrial genome, resulting in a c.100G>A (p.Gly34Ser) missense variant in the MT-CYB gene. The m.14846G>A variant is absent in both heteroplasmic and homoplasmic state ingnomAD(v3.1.1), suggesting it is not a common benign variant in the populations represented in that database. The APOGEE score for this variant is 0.67 suggesting it is possibly pathogenic. This variant is reported as Pathogenic in ClinVar (VarID:9679), and has been reported in several affected individuals in the literature with exercise intolerance, myalgia, and premature muscle fatigue [PMID:10502593, 11506394, 11782982, 14520667]. In at least one case, the level of heteroplasmy in muscle of the affected individual was significantly higher than that detected in blood [PMID:10502593]. Given its absence in population database and presence in multiple affected individuals in the literature, the apparently de novo m.14846G>A variant is reported as Likely Pathogenic, - |
Exercise intolerance Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 30, 1999 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
Hmtvar
Pathogenic
AlphaMissense
Pathogenic
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at