rs121434467
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS4_ModeratePS3_Moderate
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254841/MONDO:0044970/015
Frequency
Consequence
unassigned_transcript_4790 synonymous
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: ENST00000387365.1. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
There are no transcript annotations for this variant. | |||||||||
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MT-TI | ENST00000387365.1 | TSL:6 | n.33A>G | non_coding_transcript_exon | Exon 1 of 1 | ||||
| MT-ND2 | ENST00000361453.3 | TSL:6 | c.-175A>G | upstream_gene | N/A | ENSP00000355046.4 | |||
| MT-ND1 | ENST00000361390.2 | TSL:6 | c.*33A>G | downstream_gene | N/A | ENSP00000354687.2 |
Frequencies
Mitomap
ClinVar
ClinVar submissions as Germline
Computational scores
Source: