rs207459998

Variant names:

• chrM-14846-G-A
• rs207459998
• unassigned_transcript_4818:c.100G>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: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]

ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]

TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

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: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTB	unassigned_transcript_4818	c.100G>A	p.Gly34Ser	missense_variant	Exon 1 of 1
ND6	unassigned_transcript_4816	c.-173C>T		upstream_gene_variant
TRNE	unassigned_transcript_4817	c.-104C>T		upstream_gene_variant

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

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

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.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

Jul 23, 2021

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 30, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Jan 08, 2024

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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;