M-7465-AC-ACC
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNS1 | unassigned_transcript_4800 | c.49dupG | p.Val17fs | frameshift_variant | Exon 1 of 1 | |||
| COX2 | unassigned_transcript_4802 | c.-121_-120insC | upstream_gene_variant | |||||
| TRND | unassigned_transcript_4801 | c.-53_-52insC | upstream_gene_variant | |||||
| COX1 | unassigned_transcript_4799 | c.*20_*21insC | downstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Mitochondrial disease Pathogenic:2
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. -
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. -
not provided Pathogenic:2
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MELAS syndrome Pathogenic:2
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 -
It is observed in the gnomAD v3.1.1 (https://gnomad.broadinstitute.org/) dataset at heteroplasmic allele frequency of 0.046% and homoplasmy allele frequency of0.0089%. Predicted Consequence/Location: Mitochondrial variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15482956, 15833431, 18977334, 7581383, 9778262). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10094190, 15292920, 15482956, 17637808, 7581383, 9708714, 9778262). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1Other:1
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Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
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Deafness, sensorineural, with neurologic features Pathogenic:1
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Mitochondrial cytochrome c oxidase deficiency Pathogenic:1
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Rare genetic deafness Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at