rs387906421
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PS4PS3_Supporting
This summary comes from the ClinGen Evidence Repository: The m.14674T>C variant in MT-TE has been reported in at least 30 cases from 25 kindreds with primary mitochondrial disease. This variant is most commonly associated with reversible infantile respiratory chain deficiency (RIRCD), and has an estimated penetrance of 30% in reported families. The variant has been reported in the homoplasmic state in both affected and unaffected family members. There is one report of a heteroplasmic occurrence (90%) in a healthy mother. Age of onset in affected individuals generally ranged from birth to six weeks old, however there have been reports of weak fetal movements and one report with onset at four years old. Features include severe myopathy, feeding difficulty, and hypotonia that gradually improve over time, however mild myopathic features persist in many reported cases. Muscle biopsy findings in affected individuals include ragged red fibers, COX deficiency, and reduced respiratory chain enzyme activities in early biopsies that normalize on subsequent biopsies (PS4; PMIDs: 8155739, 19720722, 21194154, 21931168, 31333056, 33832841, 34732400, 34806237). There are no reported de novo occurrences of this variant to our knowledge. This variant is present in population databases which is to be expected given the known reduced penetrance of this variant (Mitomap: 56,910 sequences, AF=0.018%; Helix: 195,983 sequences, AF=0.006%; gnomAD v3.1.2: 56,429 sequences, AF=0.004% - homoplasmic in two individuals and heteroplasmic in three individuals). The computational predictor MitoTIP suggests this variant is pathogenic (29.4 percentile but confirmed pathogenicity) and HmtVAR predicts it to be pathogenic score of 0.8 (PP3). Several studies in skeletal muscle and primary cell cultures of affected individuals (PMID:19720722), cybrids (PMID:21194154), and transcriptome and proteomic analyses (PMID:33128823) support the functional impact of this variant (PS3_supporting). 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 January 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120581/MONDO:0044970/014
Frequency
Consequence
ENST00000387459.1 non_coding_transcript_exon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRNE | TRNE.1 use as main transcript | n.69A>G | non_coding_transcript_exon_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-TE | ENST00000387459.1 | n.69A>G | non_coding_transcript_exon_variant | 1/1 | |||||
MT-ND6 | ENST00000361681.2 | upstream_gene_variant | P1 |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Mitochondrial disease Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Wellcome Centre for Mitochondrial Research, Newcastle University | May 22, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jan 23, 2023 | The m.14674T>C variant in MT-TE has been reported in at least 30 cases from 25 kindreds with primary mitochondrial disease. This variant is most commonly associated with reversible infantile respiratory chain deficiency (RIRCD), and has an estimated penetrance of 30% in reported families. The variant has been reported in the homoplasmic state in both affected and unaffected family members. There is one report of a heteroplasmic occurrence (90%) in a healthy mother. Age of onset in affected individuals generally ranged from birth to six weeks old, however there have been reports of weak fetal movements and one report with onset at four years old. Features include severe myopathy, feeding difficulty, and hypotonia that gradually improve over time, however mild myopathic features persist in many reported cases. Muscle biopsy findings in affected individuals include ragged red fibers, COX deficiency, and reduced respiratory chain enzyme activities in early biopsies that normalize on subsequent biopsies (PS4; PMIDs: 8155739, 19720722, 21194154, 21931168, 31333056, 33832841, 34732400, 34806237). There are no reported de novo occurrences of this variant to our knowledge. This variant is present in population databases which is to be expected given the known reduced penetrance of this variant (Mitomap: 56,910 sequences, AF=0.018%; Helix: 195,983 sequences, AF=0.006%; gnomAD v3.1.2: 56,429 sequences, AF=0.004% - homoplasmic in two individuals and heteroplasmic in three individuals). The computational predictor MitoTIP suggests this variant is pathogenic (29.4 percentile but confirmed pathogenicity) and HmtVAR predicts it to be pathogenic score of 0.8 (PP3). Several studies in skeletal muscle and primary cell cultures of affected individuals (PMID: 19720722), cybrids (PMID: 21194154), and transcriptome and proteomic analyses (PMID: 33128823) support the functional impact of this variant (PS3_supporting). 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 January 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP3, PS3_supporting. - |
Mitochondrial myopathy with reversible cytochrome C oxidase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2011 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Aug 26, 2014 | - - |
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1
Likely 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.14674T>C variant in MT-TE gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS5, PP4, PP6 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at