rs207459998

Positions:

• chrM-14846-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP5_Strong

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: CYTB missense
• Scores: Apogee2 Pathogenic 0.89
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:1 EXIT-/-possibly-antiatherogenic+-poss.-myocardial-infarction-association
• Conservation: PhyloP100: 6.21

Genes affected

CYTB (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-14846-G-A is Pathogenic according to our data. Variant chrM-14846-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 9679.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYTB	unassigned_transcript_4819	c.100G>A	p.Gly34Ser	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	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

EXIT-/-possibly-antiatherogenic+-poss.-myocardial-infarction-association

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

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variant in MTCYB gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Jan 08, 2024

The m.14846G>A (p.G34S) variant in MT-CYB has been reported in one individual with primary mitochondrial disease to date (PMID: 10502593), a 52-year-old woman with exercise intolerance since childhood who later developed myalgia and extreme muscle fatigue. The variant was present at 85% heteroplasmy in muscle and was undetectable in blood, myoblasts, and skin fibroblasts. The variant was absent in blood, myoblasts, and skin fibroblasts from her two children. There was not mention of testing in extended maternal family members. 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). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.73 (Min=0, Max=1; APOGEE2 score is 0.905), which predicts a damaging effect on gene function (PP3). Single fiber testing showed higher levels of the variant in ragged red fibers (91%) than in non-ragged red fibers (17%; PS3_supporting, PMID: 10502593). In summary, this variant meets criteria to be classified as uncertain significance 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): PS3_supporting, PP3, PM2_supporting. -

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;