chrM-1606-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3PM2_SupportingPM6_SupportingPS3_Supporting
This summary comes from the ClinGen Evidence Repository: The m.1606G>A variant in MT-TV has been reported in two affected individuals in two families (PMIDs: 9450773, 2056939), however haplogroups were not provided as necessary to apply PS4_supporting. These two individuals had strikingly similar courses, as both were males who were relatively healthy until their 20s/30s when they developed progressive cognitive impairment. Other features seen in both men include bilateral cataracts, bilateral SNHL, imbalance/ataxia, and basal ganglia classifications, with both men harboring the variant at 67-70% heteroplasmy. This variant occurred de novo in one individual (absent in blood and urine from mother and brother; PM6_supporting, PMID:12056939). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at <10% in muscle, however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX negative fibers (85%) than in COX positive fibers (57%), p<0.0001 (PS3_supporting, PMID:9450773). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 73.6%, as does HmtVar with a score of 0.9 (PP3). 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 Mitochondrial Disease Variant Curation Expert Panel on June 27, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM6_supporting, PS3_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120536/MONDO:0044970/014
Frequency
Consequence
ENST00000387342.1 non_coding_transcript_exon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNV | TRNV.1 use as main transcript | n.5G>A | non_coding_transcript_exon_variant | 1/1 | ||||
| RNR1 | RNR1.1 use as main transcript | downstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MT-TV | ENST00000387342.1 | n.5G>A | non_coding_transcript_exon_variant | 1/1 | ||||||
| MT-RNR1 | ENST00000389680.2 | downstream_gene_variant |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Ataxia, progressive seizures, mental deterioration, and hearing loss Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2002 | - - |
MELAS syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Jul 12, 2019 | The NC_012920.1:m.1606G>A variant in MT-TV gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PS5, PM7 - |
Mitochondrial disease Uncertain:1
| Uncertain significance, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jun 30, 2022 | The m.1606G>A variant in MT-TV has been reported in two affected individuals in two families (PMIDs: 9450773, 2056939), however haplogroups were not provided as necessary to apply PS4_supporting. These two individuals had strikingly similar courses, as both were males who were relatively healthy until their 20s/30s when they developed progressive cognitive impairment. Other features seen in both men include bilateral cataracts, bilateral SNHL, imbalance/ataxia, and basal ganglia classifications, with both men harboring the variant at 67-70% heteroplasmy. This variant occurred de novo in one individual (absent in blood and urine from mother and brother; PM6_supporting, PMID: 12056939). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at <10% in muscle, however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX negative fibers (85%) than in COX positive fibers (57%), p<0.0001 (PS3_supporting, PMID: 9450773). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 73.6%, as does HmtVar with a score of 0.9 (PP3). 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 Mitochondrial Disease Variant Curation Expert Panel on June 27, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PS3_supporting, PM2_supporting, PP3. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at