Submissions for variant NC_012920.1(MT-TI):m.4295A>G

dbSNP: rs121434467

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV005251026	SCV005901632	uncertain significance	Mitochondrial disease	2023-12-11	reviewed by expert panel	curation	The m.4295A>G variant in MT-TI has been reported in at least four families from different ethnic groups with features of primary mitochondrial disease including deafness, hearing loss, and cardiomyopathy (PMIDs: 18177739, 22241583, 33398350, 34991096, 8889580; PS4_moderate). Of note, other isolated phenotypes have been reported including essential hypertension and autism spectrum disorder, but these are outside the scope of this curation (PMIDs: 11406419, 19778529, 19043581). This variant is seen in the general population (<0.5% in three large population databases: Mitomap - 112/61168, gnomAD v3.1.2 - 167/56431, and Helix - 923/195983). Notably, these occurrences are almost exclusively in haplogroup (hg) K (110/112 in specifically K1a in Mitomap; 166/167 in hg K in gnomAD, 911/923 in K in Helix) and these three databases combined reported only 15 individuals from non-K haplogroups (H, I, R, X, J, U, and V). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly benign (0.44) but HmtVAR predicts it to be pathogenic (0.75). Of note, this variant is 100% conserved among 45 species ranging from Drosophila to Homo sapiens in the extraordinarily conserved anticodon loop of tRNA Isoleucine. Cybrid studies showed multiple deleterious biochemical impacts of the variant in a Chinese family from haplogroup D4j (PMID: 33398350). Other studies showed this variant reduces the efficiency with which tRNAIle can be processed by 3′-tRNase (PMID: 18177739). An in-vitro system utilizing plasmids with tRNAIle inserts showed that this variant reduces the tRNase Z reaction 10.3-fold (PMID: 12655007). On the basis of these strong, independent, and consistent functional studies, this Expert Panel elected to give higher weight to this line of evidence (PS3_moderate). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note there was much discussion of the possible differing roles of this variant in haplogroups K1a (protective or tolerated) and D4j (damaging), however the VCEP elected to keep the classification of this variant as uncertain significance (four of 11 experts felt likely benign was the more appropriate classification). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 11, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_moderate.
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	MELAS syndrome	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	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	Mitochondrial non-syndromic sensorineural hearing loss	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 ).