M-7465-A-AC
Variant summary
Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PS4PS3_SupportingPP1_Moderate
This summary comes from the ClinGen Evidence Repository: The m.7471dup variant in MT-TS1 has been reported in >16 unrelated individuals with primary mitochondrial disease across several haplogroups. This variant is most commonly associated with sensorineural hearing loss however affected individuals can also have other features. Affected individuals have been reported with features including MELAS, cerebellar ataxia, myoclonus, epilepsy, white matter disease, intellectual disability, cerebellar atrophy, exercise intolerance, and hypotonia; and this variant has been seen in affected individuals in the homoplasmic and heteroplasmic states (PS4; PMIDs: 7581383, 9708714, 9832034, 9778262, 9778273, 10094190, 15482956, 11378827, 15292920, 15482956, 11378827, 15292920, 1533431, 16368237, 17637808, 15833431, 16368237). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate, PMIDs: 7581383, 9708714). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID:10545608). There are no de novo occurrences to our knowledge. There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature, have reduced penetrance, and/or variants that are insertions. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied(PMID:32906214): PS4, PP1_moderate, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA214937/MONDO:0044970/014
Frequency
Consequence
ENST00000387416.2 non_coding_transcript_exon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNS1 | TRNS1.1 use as main transcript | n.49_50insG | non_coding_transcript_exon_variant | 1/1 | ||||
| COX1 | COX1.1 use as main transcript | downstream_gene_variant | YP_003024028.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MT-TS1 | ENST00000387416.2 | n.49_50insG | non_coding_transcript_exon_variant | 1/1 | ||||||
| MT-CO1 | ENST00000361624.2 | downstream_gene_variant | ENSP00000354499 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Mitochondrial disease Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 20, 2023 | The MT-TS1 m.7465dup (n.49dup) variant, also referred to as m.7471dup and m.7472insC in the literature, results in the insertion of a nucleotide at position m.7465. Across a selection of available literature, this variant has been reported in at least 22 unrelated individuals with primary mitochondrial disease across several haplogroups (PMID: 7581383; 9708714; 9778262; 9778273; 9832034; 10094190; 11378827; 15292920; 15482956; 15833431; 16368237; 17637808). This variant has been associated with isolated sensorineural hearing loss; however, affected individuals can also have other features including MELAS, cerebellar ataxia, myoclonus, epilepsy, white matter disease, intellectual disability, cerebral and cerebellar atrophy, exercise intolerance, and hypotonia. This variant has been seen in affected individuals in homoplasmic and heteroplasmic states. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PMIDs: 9708714; 10094190; 15833431; 16368237). The variant is reported in the Genome Aggregation Database (version 3.1.2) at a homoplasmic frequency of 0.000089 and a heteroplasmic frequency of 0.000462, which may be consistent with reduced penetrance and tissue-specific heteroplasmy of the variant. Cybrid studies supported the functional impact of this variant (PMID: 10545608). Based on the available evidence, the m.7465dup (n.49dup) variant is classified as pathogenic for primary mitochondrial disease. - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Nov 14, 2022 | The m.7471dup variant in MT-TS1 has been reported in >16 unrelated individuals with primary mitochondrial disease across several haplogroups. This variant is most commonly associated with sensorineural hearing loss however affected individuals can also have other features. Affected individuals have been reported with features including MELAS, cerebellar ataxia, myoclonus, epilepsy, white matter disease, intellectual disability, cerebellar atrophy, exercise intolerance, and hypotonia; and this variant has been seen in affected individuals in the homoplasmic and heteroplasmic states (PS4; PMIDs: 7581383, 9708714, 9832034, 9778262, 9778273, 10094190, 15482956, 11378827, 15292920, 15482956, 11378827, 15292920, 1533431, 16368237, 17637808, 15833431, 16368237). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate, PMIDs: 7581383, 9708714). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 10545608). There are no de novo occurrences to our knowledge. There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature, have reduced penetrance, and/or variants that are insertions. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied(PMID: 32906214): PS4, PP1_moderate, PS3_supporting. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Dec 18, 2023 | - - |
Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1Other:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2001 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Deafness, sensorineural, with neurologic features Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2001 | - - |
Rare genetic deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 04, 2011 | The 7471_7472insC variant in the MTTS1 gene has been reported in 14 probands aff ected with either hearing loss, neurological abnormalities, or both, is absent i n 1381 controls, and cosegregates with disease in affected family members (Tiran ti 1995, Ensinke 1998, Jaksch 1998, Verhoeven 1999, Fetoni 2004, Jacobs 2005, Pu lkes 2005, Cardaioli 2006, Leveque 2007, Swalwell 2008, Valente 2009). In additi on, functional analyses of muscle biopsies from affected individuals and in vitr o mitochondrial clones harboring the variant reveal deficiency in COX and defect ive mitochondrial respiration (Tiranti 1995, Jaksch 1998, Fetoni 2004, Pulkes 20 05, Valente 2009). In summary, this variant meets our criteria to be classified as pathogenic. - |
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke 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.7471dupC variant in MT-TS1 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 - |
Mitochondrial cytochrome c oxidase deficiency Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2001 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at