Submissions for variant NC_012920.1(MT-TI):m.4300A>G

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Minimum conflict level: Report conflict between different conditions
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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV002291210	SCV002583532	likely pathogenic	Mitochondrial disease	2022-09-12	reviewed by expert panel	curation	The m.4300A>G variant in MT-TI has been reported in at least 17 individuals from eight families with hypertrophic cardiomyopathy. Affected individuals had variable ages of onset (11 months old to 40s). All cases developed hypertrophic cardiomyopathy. Muscle biopsy revealed COX negative fibers in cardiac tissue and one case had ragged red fibers in skeletal muscle. Heteroplasmy levels were predominantly the same in all affected probands as the variant was present at homoplasmy or > 97% in all tissues. Other affected family members did harbor the variant at 60-100%. Of note, some healthy family members had the variant ranging from 40-100% (PS4_moderate; PMIDs: 10065021, 7646516, 12767666, 12711217, 23847141). This variant segregated with disease in a family with LVH with diffuse hypertrophy as the proband's heteroplasmy was 98% in heart, 85% in muscle, and 95% in blood. His seven affected maternal relatives had heteroplasmy levels ranging from 60-92% in blood. His 12 unaffected relatives available for testing heteroplasmy ranged 50-78% in blood (PP1_moderate, PMID: 1006502). There are no reported de novo occurrences of this variant to our knowledge. There are three occurrences of this variant in Helix dataset (frequency of 0.001%) that includes two homoplasmic and one heteroplasmic individuals. This variant is absent in gnomAD v3.1.2 and in GenBank dataset therefore the frequency is still low enough to meet criteria for PM2_supporting. There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor MitoTIP suggests this variant is pathogenic (79.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic 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 September 12, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM2_supporting, PP3, PP1_moderate.
Mendelics	RCV002247293	SCV002517699	pathogenic	MERRF syndrome	2022-05-04	criteria provided, single submitter	clinical testing
OMIM	RCV000010229	SCV000030453	pathogenic	Primary familial hypertrophic cardiomyopathy	2003-05-21	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001251031	SCV001426424	likely pathogenic	Primary dilated cardiomyopathy; Asymmetric septal hypertrophy	2018-01-01	no assertion criteria provided	research

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