rs207459998

chrM-14846-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_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
• Scores: Apogee2 Pathogenic 0.89
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 EXIT-/-possibly-antiatherogenic+-poss.-myocardial-infarction-association
• Conservation: PhyloP100: 6.21

Genes affected

CYTB (HGNC:):

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]

ACMG classification

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	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

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

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.89
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.66

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs207459998; hg19: chrM-14847; COSMIC: COSV62378345; COSMIC: COSV62378345;