ClinVar Miner

Submissions for variant m.4295A>G (rs121434467)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224071 SCV000281548 uncertain significance not provided 2015-01-19 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000224071 SCV000884154 uncertain significance not provided 2017-12-22 criteria provided, single submitter clinical testing The m.4295A>G variant (rs121434467) is located at position 33 of the tRNA-isoleucine gene. Although this variant has been reported in patients with diverse symptoms including hypertrophic cardiomyopathy, encephalopathy, non-syndromic hearing loss, occipital stroke and essential hypertension, a consistent clinical presentation has not been identified (Finnila 2001, Gutierrez Cortes 2012, Li 2008, Merante 1996, Zhu 2009). Functional characterization of the variant tRNA indicates a defect in 3' processing (Levinger 2003), resulting in reduced activity of complex III in oxidative phosphorylation; however, the clinical relevance of these observations in not known (Gutierrez Cortes 2012, Merante 1996). Furthermore, the m.4295A>G variant is observed in 10 percent of individuals with the mitochondrial haplogroup K1a (87 out of 916 individual in the MITOMAP database). Therefore, based on the available information, the clinical significance of the m.4295A>G variant cannot be determined with certainty.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000850718 SCV000992951 benign Juvenile myopathy, encephalopathy, lactic acidosis AND stroke 2019-07-12 criteria provided, single submitter clinical testing The NC_012920.1:m.4295A>G variant in MT-TI gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS1, BS4
Athena Diagnostics Inc RCV000224071 SCV001144615 uncertain significance not provided 2019-03-22 criteria provided, single submitter clinical testing
OMIM RCV000010226 SCV000030450 pathogenic Primary familial hypertrophic cardiomyopathy 2012-04-01 no assertion criteria provided literature only
OMIM RCV000022900 SCV000044191 pathogenic Deafness, nonsyndromic sensorineural, mitochondrial 2012-04-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223744 SCV000280195 uncertain significance not specified no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MTTI m.4295A>G Merante et al (1996) report the variant in two siblings with severe HCM and their mother who was phenotype negative. The proband presented at 7 months of age with cyanosis and died due to complications of HCM. Autopsy revealed proliferation of mitochondria in the heart, so the authors looked for mitochondrial variants. Notably, they did only a limited analysis of mitochondrial DNA; they sequenced tRNA genes and looked for gross deletions and duplications. The proband, who had the most severe presentation, had a >90 % heteroplasmic load in the heart, her brother had 89% variant load in the heart and developed HCM at age 4 while their mother who had a variant load of 79% in the cardiac muscle was phenotype negative for HCM but did have reduced respiratory chain activity levels. Adenosine is highly conserved at position 4295 across species. This variant has been reported in individuals from the general population: 5/2704 individuals in mtDB (www.genpath.uu.se/mtDB); 2/3735 individuals in MitoWheel (http://mitowheel.org/mitowheel.html ).

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