Submissions for variant NC_012920.1(MT-CYB):m.14846G>A

dbSNP: rs207459998

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV004791206	SCV005407799	uncertain significance	Mitochondrial disease	2024-01-08	reviewed by expert panel	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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000855169	SCV000998219	pathogenic	Mitochondrial myopathy with reversible cytochrome C oxidase deficiency	2019-10-17	criteria provided, single submitter	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variant in MTCYB gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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
New York Genome Center	RCV002265553	SCV002548620	likely pathogenic	MT-CYB associated Exercise intolerance; MT-CYB associated Mitochondrial myopathy	2021-07-23	criteria provided, single submitter	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,
OMIM	RCV000010317	SCV000030542	pathogenic	Exercise intolerance	1999-09-30	no assertion criteria provided	literature only