rs199474821
Variant summary
Our verdict is Likely pathogenic. Variant got 5 ACMG points: 5P and 0B. PP3PS3_ModeratePS4_Moderate
This summary comes from the ClinGen Evidence Repository: The m.7511T>C variant in MT-TS1 has been reported in ten unrelated probands from ten kindreds of varying ethnic background with nonsyndromic sensorineural hearing loss (PS4_moderate; PMIDs: 10371545, 12461693, 15670746, 18340555, 26279247, 25968158, 28320335, 29257206). In these families, the variant is present in family members with and without hearing loss. Hearing loss was variable overall when present, ranging from mild to profound. Age of onset of hearing loss varied from childhood to adulthood. Hearing loss was stable in some individuals and progressive in others. Some individuals also reported tinnitus and vertigo. There has been no other organ system involvement reported to date (although it is not clear if other organ systems were assessed in affected individuals). Muscle biopsy was not routinely performed in affected individuals however one individual did have COX-deficient fibers and complex IV deficiency (PMID:10371545). The variant was generally present at homoplasmy (in maternal family members with and without hearing loss), however there were some heteroplasmic occurrences (PMIDs: 10371545, 12461693, 15670746, 26279247, 29257206). Penetrance differed across reported families, and several modifying factors were discussed, including variants in the genes PCDH15 (PMID:26279247) and YARS2 (PMID:25968158). Affected and unaffected individuals in these families had the variant and there was no correlation between severity and heteroplasmy level, thus preventing consideration for PP1. There are no de novo occurrences of this variant reported to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (78.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. Single fiber testing (PMID:10371545) and cybrid analysis (PMID:14960712) support the pathogenicity of this variant (PS3_moderate), as do other functional assays performed (PMIDs: 31685661, 16361254). This variant meets criteria to be classified as of uncertain significance however this Expert Panel elected to modify the classification to likely pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common mitochondrial variants associated with nonsyndromic hearing loss. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 30, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PS3_moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340922/MONDO:0044970/014
Frequency
Consequence
ENST00000387416.2 non_coding_transcript_exon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 5 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNS1 | TRNS1.1 use as main transcript | n.4A>G | non_coding_transcript_exon_variant | 1/1 | ||||
| TRND | TRND.1 use as main transcript | upstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MT-TS1 | ENST00000387416.2 | n.4A>G | non_coding_transcript_exon_variant | 1/1 | ||||||
| MT-TD | ENST00000387419.1 | upstream_gene_variant |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2002 | - - |
Mitochondrial disease Pathogenic:1
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Nov 30, 2022 | The m.7511T>C variant in MT-TS1 has been reported in ten unrelated probands from ten kindreds of varying ethnic background with nonsyndromic sensorineural hearing loss (PS4_moderate; PMIDs: 10371545, 12461693, 15670746, 18340555, 26279247, 25968158, 28320335, 29257206). In these families, the variant is present in family members with and without hearing loss. Hearing loss was variable overall when present, ranging from mild to profound. Age of onset of hearing loss varied from childhood to adulthood. Hearing loss was stable in some individuals and progressive in others. Some individuals also reported tinnitus and vertigo. There has been no other organ system involvement reported to date (although it is not clear if other organ systems were assessed in affected individuals). Muscle biopsy was not routinely performed in affected individuals however one individual did have COX-deficient fibers and complex IV deficiency (PMID: 10371545). The variant was generally present at homoplasmy (in maternal family members with and without hearing loss), however there were some heteroplasmic occurrences (PMIDs: 10371545, 12461693, 15670746, 26279247, 29257206). Penetrance differed across reported families, and several modifying factors were discussed, including variants in the genes PCDH15 (PMID: 26279247) and YARS2 (PMID: 25968158). Affected and unaffected individuals in these families had the variant and there was no correlation between severity and heteroplasmy level, thus preventing consideration for PP1. There are no de novo occurrences of this variant reported to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (78.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. Single fiber testing (PMID: 10371545) and cybrid analysis (PMID: 14960712) support the pathogenicity of this variant (PS3_moderate), as do other functional assays performed (PMIDs: 31685661, 16361254). This variant meets criteria to be classified as of uncertain significance however this Expert Panel elected to modify the classification to likely pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common mitochondrial variants associated with nonsyndromic hearing loss. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 30, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_moderate, PP3. - |
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
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.7511T>C 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, PM7 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at