ClinVar Genomic variation as it relates to human health
NM_004958.4(MTOR):c.5930C>T (p.Thr1977Ile)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004958.4(MTOR):c.5930C>T (p.Thr1977Ile)
Variation ID: 584432 Accession: VCV000584432.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.22 1: 11128107 (GRCh38) [ NCBI UCSC ] 1: 11188164 (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 Oct 10, 2018 Feb 14, 2024 Apr 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004958.4:c.5930C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004949.1:p.Thr1977Ile missense NC_000001.11:g.11128107G>A NC_000001.10:g.11188164G>A NG_033239.1:g.139445C>T LRG_734:g.139445C>T LRG_734t1:c.5930C>T - Protein change
- T1977I
- Other names
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- Canonical SPDI
- NC_000001.11:11128106:G:A
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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
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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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MTOR | - | - |
GRCh38 GRCh37 |
2365 | 2546 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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MTOR-related megalencephaly and pigmentary mosaicism in skin
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Pathogenic (1) |
criteria provided, single submitter
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May 11, 2018 | RCV000708565.2 |
Pathogenic (1) |
criteria provided, single submitter
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Aug 23, 2019 | RCV000991198.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2020 | RCV001260509.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 22, 2023 | RCV001384597.8 |
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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Pathogenic
(May 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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MTOR-related megalencephaly and pigmentary mosaicism in skin
(Somatic mutation)
Affected status: yes
Allele origin:
de novo
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000837682.2 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
A mosaic c.5930C>T (p.T1977I) pathogenic variant in the MTOR gene was detected in this individual (level of mosaicism 32%, 55 mutant and 117 reference reads). … (more)
A mosaic c.5930C>T (p.T1977I) pathogenic variant in the MTOR gene was detected in this individual (level of mosaicism 32%, 55 mutant and 117 reference reads). This variant has been previously reported as mosaic in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin [PMID 27159400]. This variant has also been seen as mosaic in one internal patient with macrocephaly, overgrowth, and other similar symptoms. This individual has been reported in PMID: 30569621. (less)
Number of individuals with the variant: 1
Clinical Features:
Wide anterior fontanel (present) , Vertebral arch anomaly (present) , Ventriculomegaly (present) , Tapered finger (present) , Severe receptive language delay (present) , Severe global … (more)
Wide anterior fontanel (present) , Vertebral arch anomaly (present) , Ventriculomegaly (present) , Tapered finger (present) , Severe receptive language delay (present) , Severe global developmental delay (present) , Severe expressive language delay (present) , Premature birth following premature rupture of fetal membranes (present) , Premature birth (present) , Polymicrogyria (present) , Pointed chin (present) , Morphological abnormality of the central nervous system (present) , Maternal diabetes (present) , Macrocephaly at birth (present) , Macrocephalus (present) , Low-set ears (present) , Linear hyperpigmentation (present) , Irregular hyperpigmentation of back (present) , Irregular hyperpigmentation (present) , Hypoplastic labia majora (present) , Hypoplasia of the corpus callosum (present) , Hyperpigmented streaks (present) , Hyperpigmentation of the skin (present) , Gray matter heterotopias (present) , Generalized hypotonia (present) , Extra-axial cerebrospinal fluid accumulation (present) , Dysplastic corpus callosum (present) , Depressed nasal bridge (present) , Delayed speech and language development (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Delayed ability to stand (present) , Delayed ability to sit (present) , Constipation (present) , Communicating hydrocephalus (present) , Cervical spinal canal stenosis (present) , Calcaneovalgus deformity (present) , Aqueductal stenosis (present) , Anteverted nares (present) , Abnormality of neuronal migration (present) , Abnormal cortical gyration (present) (less)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Asian
Tissue: fibroblasts
Comment on evidence:
Condition (and other patients with the same mosaic variant) described in PMID:27159400.
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2018-05-11
Testing laboratory interpretation: Pathogenic
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Pathogenic
(Aug 23, 2019)
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criteria provided, single submitter
Method: clinical testing
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Isolated focal cortical dysplasia type II
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Undiagnosed Diseases Network, NIH
Accession: SCV001142575.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Observation 1:
Clinical Features:
Wide intermamillary distance (present) , Seizures (present) , Prominent forehead (present) , Profound global developmental delay (present) , Optic disc drusen (present) , No social … (more)
Wide intermamillary distance (present) , Seizures (present) , Prominent forehead (present) , Profound global developmental delay (present) , Optic disc drusen (present) , No social interaction (present) , Myopia (present) , Megalencephaly (present) , Macular hypopigmented whorls, streaks, and patches (present) , Macrocephalus (present) , Irritability (present) , Infantile spasms (present) , Inability to walk (present) , Hypoplasia of the corpus callosum (present) , Hypopigmentation of the skin (present) , Hyperpigmented/hypopigmented macules (present) , Hyperpigmentation of the skin (present) , Hyperextensibility at wrists (present) , Hyperextensibility at elbow (present) , Hydrocephalus (present) , Heterotopia (present) , Generalized tonic-clonic seizures (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Epileptic spasms (present) , EEG with generalized slow activity (present) , Dolichocephaly (present) , Constipation (present) , Cortical visual impairment (present) , Alternating exotropia (present) , Absent speech (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Asian
Tissue: fibroblasts
Observation 2:
Clinical Features:
Wide anterior fontanel (present) , Vertebral arch anomaly (present) , Ventriculomegaly (present) , Tapered finger (present) , Severe receptive language delay (present) , Severe global … (more)
Wide anterior fontanel (present) , Vertebral arch anomaly (present) , Ventriculomegaly (present) , Tapered finger (present) , Severe receptive language delay (present) , Severe global developmental delay (present) , Severe expressive language delay (present) , Premature birth following premature rupture of fetal membranes (present) , Premature birth (present) , Polymicrogyria (present) , Pointed chin (present) , Morphological abnormality of the central nervous system (present) , Maternal diabetes (present) , Macrocephaly at birth (present) , Macrocephalus (present) , Low-set ears (present) , Linear hyperpigmentation (present) , Irregular hyperpigmentation of back (present) , Irregular hyperpigmentation (present) , Hypoplastic labia majora (present) , Hypoplasia of the corpus callosum (present) , Hyperpigmented streaks (present) , Hyperpigmentation of the skin (present) , Gray matter heterotopias (present) , Generalized hypotonia (present) , Extra-axial cerebrospinal fluid accumulation (present) , Dysplastic corpus callosum (present) , Depressed nasal bridge (present) , Delayed speech and language development (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Delayed ability to stand (present) , Delayed ability to sit (present) , Constipation (present) , Communicating hydrocephalus (present) , Cervical spinal canal stenosis (present) , Calcaneovalgus deformity (present) , Aqueductal stenosis (present) , Anteverted nares (present) , Abnormality of neuronal migration (present) , Abnormal cortical gyration (present) (less)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Asian
Tissue: fibroblasts
Comment on evidence:
A mosaic c.5930C>T (p.T1977I) pathogenic variant in the MTOR gene was detected in this individual (level of mosaicism 32%, 55 mutant and 117 reference reads). … (more)
A mosaic c.5930C>T (p.T1977I) pathogenic variant in the MTOR gene was detected in this individual (level of mosaicism 32%, 55 mutant and 117 reference reads). This variant has been previously reported as mosaic in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin [PMID 27159400]. This variant has also been seen as mosaic in one internal patient with macrocephaly, overgrowth, and other similar symptoms. (less)
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Pathogenic
(Sep 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities
Affected status: yes
Allele origin:
somatic
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001437530.1
First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020 |
Observation 1: Observation 2: Observation 3: |
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Pathogenic
(Jul 05, 2022)
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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: SCV002546733.2
First in ClinVar: Jul 17, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate constitutive activation of mTOR complex 1 and enlarged neuronal size (Mirzaa et al., 2016); Not observed in large population cohorts (gnomAD); … (more)
Published functional studies demonstrate constitutive activation of mTOR complex 1 and enlarged neuronal size (Mirzaa et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27159400, 30569621) (less)
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Pathogenic
(Apr 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001584148.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MTOR function (PMID: 27159400). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MTOR function (PMID: 27159400). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MTOR protein function. ClinVar contains an entry for this variant (Variation ID: 584432). This missense change has been observed in individuals with clinical features of MTOR-related conditions (PMID: 27159400, 30569621, 33833411). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1977 of the MTOR protein (p.Thr1977Ile). (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities. | Carmignac V | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33833411 |
Recurrent mosaic MTOR c.5930C > T (p.Thr1977Ile) variant causing megalencephaly, asymmetric polymicrogyria, and cutaneous pigmentary mosaicism: Case report and review of the literature. | Handoko M | American journal of medical genetics. Part A | 2019 | PMID: 30569621 |
Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism. | Mirzaa GM | JAMA neurology | 2016 | PMID: 27159400 |
Text-mined citations for rs587777893 ...
HelpRecord last updated Feb 20, 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.