The c.971C>T (p.Thr324Ile) variant in MSTO1 is a nonsense variant. This variant was identified as a compound heterozygote with c.676C>T (p.Gln226Ter). The variant is seen in 13 individual in gnomAD as a heterozygote and has been reported in a similarly affected patient.
ClinVar Genomic variation as it relates to human health
NM_018116.4(MSTO1):c.971C>T (p.Thr324Ile)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_018116.4(MSTO1):c.971C>T (p.Thr324Ile)
Variation ID: 438833 Accession: VCV000438833.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155612848 (GRCh38) [ NCBI UCSC ] 1: 155582639 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 28, 2017 Sep 29, 2024 Jun 3, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_018116.4:c.971C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060586.2:p.Thr324Ile missense NM_001256532.1:c.971C>T NP_001243461.1:p.Thr324Ile missense NM_001256533.1:c.971C>T NP_001243462.1:p.Thr324Ile missense NM_001350772.1:c.971C>T NP_001337701.1:p.Thr324Ile missense NM_001350773.1:c.971C>T NP_001337702.1:p.Thr324Ile missense NM_001350774.1:c.971C>T NP_001337703.1:p.Thr324Ile missense NM_001350775.1:c.971C>T NP_001337704.1:p.Thr324Ile missense NM_001350776.1:c.806C>T NP_001337705.1:p.Thr269Ile missense NM_001350777.1:c.440C>T NP_001337706.1:p.Thr147Ile missense NM_001350778.1:c.440C>T NP_001337707.1:p.Thr147Ile missense NM_001350779.1:c.440C>T NP_001337708.1:p.Thr147Ile missense NM_001350780.1:c.437C>T NP_001337709.1:p.Thr146Ile missense NM_001350781.1:c.437C>T NP_001337710.1:p.Thr146Ile missense NM_001350782.1:c.437C>T NP_001337711.1:p.Thr146Ile missense NM_001350783.1:c.437C>T NP_001337712.1:p.Thr146Ile missense NM_001350784.1:c.428C>T NP_001337713.1:p.Thr143Ile missense NM_001350785.1:c.428C>T NP_001337714.1:p.Thr143Ile missense NM_001350786.1:c.437C>T NP_001337715.1:p.Thr146Ile missense NM_001350787.1:c.428C>T NP_001337716.1:p.Thr143Ile missense NM_001350788.1:c.437C>T NP_001337717.1:p.Thr146Ile missense NM_001350789.1:c.428C>T NP_001337718.1:p.Thr143Ile missense NR_046292.1:n.1172C>T non-coding transcript variant NR_046293.1:n.1114C>T non-coding transcript variant NR_046294.1:n.1036C>T non-coding transcript variant NR_046295.1:n.974C>T non-coding transcript variant NR_146907.1:n.1050C>T non-coding transcript variant NR_146908.1:n.1088C>T non-coding transcript variant NC_000001.11:g.155612848C>T NC_000001.10:g.155582639C>T - Protein change
- T324I, T146I, T147I, T143I, T269I
- Other names
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- Canonical SPDI
- NC_000001.11:155612847:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| MSTO1 | - | - |
GRCh38 GRCh37 |
165 | 190 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 3, 2022 | RCV000505816.8 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Jun 28, 2024 | RCV001266925.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 3, 2024 | RCV001788237.5 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Dec 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
|
Undiagnosed Diseases Network, NIH
Accession: SCV000746659.2
First in ClinVar: Sep 28, 2017 Last updated: May 03, 2018 |
Comment:
The c.971C>T (p.Thr324Ile) variant in MSTO1 is a nonsense variant. This variant was identified as a compound heterozygote with c.676C>T (p.Gln226Ter). The variant is seen … (more)
The c.971C>T (p.Thr324Ile) variant in MSTO1 is a nonsense variant. This variant was identified as a compound heterozygote with c.676C>T (p.Gln226Ter). The variant is seen in 13 individual in gnomAD as a heterozygote and has been reported in a similarly affected patient. (less)
Number of individuals with the variant: 1
Clinical Features:
Truncal ataxia (present) , Spastic gait (present) , Slurred speech (present) , Severe expressive language delay (present) , Saccadic smooth pursuit (present) , Receptive language … (more)
Truncal ataxia (present) , Spastic gait (present) , Slurred speech (present) , Severe expressive language delay (present) , Saccadic smooth pursuit (present) , Receptive language delay (present) , Progressive cerebellar ataxia (present) , Lower limb hyperreflexia (present) , Language impairment (present) , Incoordination (present) , Growth hormone deficiency (present) , Gait disturbance (present) , Elevated serum creatine phosphokinase (present) , Cerebellar atrophy (present) (less)
Age: 10-19 years
Sex: female
Ethnicity/Population group: Asian
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Likely pathogenic
(Apr 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001623323.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
Variant summary: MSTO1 c.971C>T (p.Thr324Ile) results in a non-conservative amino acid change located in the DML1/Misato, tubulin domain of the encoded protein sequence. Three of … (more)
Variant summary: MSTO1 c.971C>T (p.Thr324Ile) results in a non-conservative amino acid change located in the DML1/Misato, tubulin domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250888 control chromosomes (gnomAD). c.971C>T has been reported in the literature in four independent indviduals carrying a second MSTO1 variant, whose clinical features overlap with Mitochondrial Myopathy-Cerebellar Ataxia-Pigmentary Retinopathy Syndrome, including delayed motor and speech development, muscle weakness, unsteady gait/poor coordination, tremor, and abnormal EMG, MRI and/or muscle biopsy (Nasca_2017, Donkervoort_2019, Jiao_2020, Lee_2020). To our knowledge, no conclusive functional/experimental studies have been performed on the variant of interest. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002059089.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000438833, PS1_S). Functional studies … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000438833, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:28544275, PS3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000043, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Elevated circulating creatine kinase concentration (present) , Depressed nasal bridge (present) , Gowers sign (present) , High, narrow palate (present) … (more)
Global developmental delay (present) , Elevated circulating creatine kinase concentration (present) , Depressed nasal bridge (present) , Gowers sign (present) , High, narrow palate (present) , Anteverted nares (present) , Waddling gait (present) (less)
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Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
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Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome
Affected status: yes
Allele origin:
inherited
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002499642.1
First in ClinVar: Jun 01, 2022 Last updated: Jun 01, 2022 |
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Likely pathogenic
(Jun 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002030986.4
First in ClinVar: Dec 12, 2021 Last updated: Sep 29, 2024 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29339779, 28544275, 31130378, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29339779, 28544275, 31130378, 30684668, 31607746, 31463572, 35598585, 33222031, 35446979, 33672784, 36468072) (less)
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Pathogenic
(Sep 22, 2017)
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no assertion criteria provided
Method: literature only
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MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000600007.1
First in ClinVar: Sep 28, 2017 Last updated: Sep 28, 2017 |
Comment on evidence:
In a boy with autosomal recessive mitochondrial myopathy and ataxia (MMYAT; 617675), Nasca et al. (2017) identified compound heterozygous mutations in the MSTO1 gene: a … (more)
In a boy with autosomal recessive mitochondrial myopathy and ataxia (MMYAT; 617675), Nasca et al. (2017) identified compound heterozygous mutations in the MSTO1 gene: a c.971C-T transition (c.971C-T, NM_018116.3) in exon 10, resulting in a thr324-to-ile (T324I) substitution, and a G-to-A transition (c.966+1G-A; 617619.0004) in intron 9, resulting in a splice site alteration. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations were found at a very low frequency in the ExAC database (less than 0.00004). Analysis of patient cells showed that the splice site mutation resulted in an aberrant transcript lacking exon 9. (less)
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Uncertain significance
(Dec 18, 2017)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older and outlier claim with insufficient supporting evidence
Source: ClinGen
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001445106.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: African American/Caucasian/Cherokee
|
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
Variant summary: MSTO1 c.971C>T (p.Thr324Ile) results in a non-conservative amino acid change located in the DML1/Misato, tubulin domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250888 control chromosomes (gnomAD). c.971C>T has been reported in the literature in four independent indviduals carrying a second MSTO1 variant, whose clinical features overlap with Mitochondrial Myopathy-Cerebellar Ataxia-Pigmentary Retinopathy Syndrome, including delayed motor and speech development, muscle weakness, unsteady gait/poor coordination, tremor, and abnormal EMG, MRI and/or muscle biopsy (Nasca_2017, Donkervoort_2019, Jiao_2020, Lee_2020). To our knowledge, no conclusive functional/experimental studies have been performed on the variant of interest. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000438833, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:28544275, PS3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000043, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29339779, 28544275, 31130378, 30684668, 31607746, 31463572, 35598585, 33222031, 35446979, 33672784, 36468072)
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The c.971C>T (p.Thr324Ile) variant in MSTO1 is a nonsense variant. This variant was identified as a compound heterozygote with c.676C>T (p.Gln226Ter). The variant is seen in 13 individual in gnomAD as a heterozygote and has been reported in a similarly affected patient.
Comment:
Variant summary: MSTO1 c.971C>T (p.Thr324Ile) results in a non-conservative amino acid change located in the DML1/Misato, tubulin domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250888 control chromosomes (gnomAD). c.971C>T has been reported in the literature in four independent indviduals carrying a second MSTO1 variant, whose clinical features overlap with Mitochondrial Myopathy-Cerebellar Ataxia-Pigmentary Retinopathy Syndrome, including delayed motor and speech development, muscle weakness, unsteady gait/poor coordination, tremor, and abnormal EMG, MRI and/or muscle biopsy (Nasca_2017, Donkervoort_2019, Jiao_2020, Lee_2020). To our knowledge, no conclusive functional/experimental studies have been performed on the variant of interest. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000438833, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:28544275, PS3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000043, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29339779, 28544275, 31130378, 30684668, 31607746, 31463572, 35598585, 33222031, 35446979, 33672784, 36468072)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Evidence of motor axon or motor neuron damage in a Chinese patient with compound heterozygous MSTO1 variants. | Jiao Y | Acta neurologica Belgica | 2021 | PMID: 33222031 |
| Diagnostic utility of transcriptome sequencing for rare Mendelian diseases. | Lee H | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31607746 |
| MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement. | Donkervoort S | Acta neuropathologica | 2019 | PMID: 31463572 |
| Recessive mutations in MSTO1 cause mitochondrial dynamics impairment, leading to myopathy and ataxia. | Nasca A | Human mutation | 2017 | PMID: 28544275 |
Text-mined citations for rs622288 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.