M-7465-AC-ACC
Variant summary
Our verdict is Pathogenic. The variant received 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
unassigned_transcript_4800 frameshift
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 7 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 |
|---|---|---|---|---|---|---|---|---|---|---|
| MT-TS1 | ENST00000387416.2 | n.49dupG | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 | |||||
| MT-CO2 | ENST00000361739.1 | c.-121_-120insC | upstream_gene_variant | 6 | ENSP00000354876.1 | |||||
| MT-CO1 | ENST00000361624.2 | c.*20_*21insC | downstream_gene_variant | 6 | ENSP00000354499.2 | |||||
| MT-TD | ENST00000387419.1 | n.-53_-52insC | upstream_gene_variant | 6 |
Frequencies
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
MELAS syndrome Pathogenic:2
The variant is observed in the gnomAD v4.1.0 dataset (total allele frequency: 0.046%, homoplasmic allele frequency: 0.009%). 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). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 10094190, 15482956, 17637808, 9708714, 9778262). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (3billion dataset/ClinVar ID: VCV000042226). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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 non-syndromic sensorineural hearing loss Pathogenic:1Other:1
MERRF syndrome Pathogenic:1
Criteria applied: PS4, PP1_MOD, PS3_SUP
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
Deafness, sensorineural, with neurologic features Pathogenic:1
Mitochondrial cytochrome c oxidase deficiency Pathogenic:1
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: