rs207459998

Variant names:

• chrM-14846-G-A
• rs207459998
• ENST00000361789.2:c.100G>A
• MT-CYB p.Gly34Ser

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120617/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CYB ENST00000361789.2 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
• Publications: 16 publications found

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]

MT-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)

TRNE Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361789.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CYB	ENST00000361789.2	TSL:6	c.100G>A	p.Gly34Ser	missense	Exon 1 of 1	ENSP00000354554.2	P00156
	MT-ND6	ENST00000361681.2	TSL:6	c.-173C>T		upstream_gene	N/A	ENSP00000354665.2	P03923
	MT-TE	ENST00000387459.1	TSL:6	n.-104C>T		upstream_gene	N/A

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): EXIT-/-possibly-antiatherogenic+-poss.-myocardial-infarction-association

Status: Reported-[VUS]

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Exercise intolerance (1)
-	1	-	Mitochondrial disease (1)
1	-	-	Mitochondrial myopathy with reversible cytochrome C oxidase deficiency (1)
1	-	-	MT-CYB associated Exercise intolerance;na:MT-CYB associated Mitochondrial myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.89
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.66
PhyloP100		6.2
Mutation Taster		=7/93	disease causing

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs207459998;

hg19: chrM-14847;

COSMIC: COSV62378345;

COSMIC: COSV62378345;