ClinVar Genomic variation as it relates to human health
NM_014975.3(MAST1):c.1549G>A (p.Gly517Ser)
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_014975.3(MAST1):c.1549G>A (p.Gly517Ser)
Variation ID: 599361 Accession: VCV000599361.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12865089 (GRCh38) [ NCBI UCSC ] 19: 12975903 (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 Jan 14, 2019 Mar 16, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014975.3:c.1549G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055790.1:p.Gly517Ser missense NC_000019.10:g.12865089G>A NC_000019.9:g.12975903G>A NG_054729.1:g.36159G>A - Protein change
- G517S
- Other names
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- Canonical SPDI
- NC_000019.10:12865088: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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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
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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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MAST1 | - | - |
GRCh38 GRCh37 |
348 | 469 |
Conditions - Germline
Condition
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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
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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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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 20, 2023 | RCV000735992.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 18, 2022 | RCV001655589.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 6, 2024 | RCV003892681.1 |
Submissions - Germline
Classification
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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
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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
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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
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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
(Jun 11, 2021)
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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: SCV001871043.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32901917, 32198973, 30449657, 30842224) (less)
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Pathogenic
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002011921.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least two similarly affected unrelated … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least two similarly affected unrelated individuals (ClinVar ID: VCV000599361.3, PMID: 30449657, PS2 and PS4_M). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.822, 3Cnet: 0.994, PP3). Patient's phenotype is considered compatible with Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebellar vermis hypoplasia (present) , Nystagmus (present) , Hypoplasia of the corpus callosum (present) , Delayed speech and language development (present) , Delayed gross motor … (more)
Cerebellar vermis hypoplasia (present) , Nystagmus (present) , Hypoplasia of the corpus callosum (present) , Delayed speech and language development (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Intellectual disability (present) , Generalized hypotonia (present) (less)
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Pathogenic
(Apr 20, 2023)
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criteria provided, single submitter
Method: research
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Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations
Affected status: yes
Allele origin:
de novo
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Duke University Health System Sequencing Clinic, Duke University Health System
Accession: SCV003918978.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
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Pathogenic
(Nov 18, 2022)
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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: SCV004551776.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 599361). This missense change has been observed in individual(s) with mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCHCM) (PMID: 30449657, 32901917). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 517 of the MAST1 protein (p.Gly517Ser). (less)
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Pathogenic
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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MAST1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004713101.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The MAST1 c.1549G>A variant is predicted to result in the amino acid substitution p.Gly517Ser. This variant has been reported in the de novo state in … (more)
The MAST1 c.1549G>A variant is predicted to result in the amino acid substitution p.Gly517Ser. This variant has been reported in the de novo state in individuals with Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (Tripathy et al. 2018. PubMed ID: 30449657; Seo et al. 2020. PubMed ID: 32901917. Supplementary 2). This variant has also been reported in the de novo state in a patient with atypical Rett syndrome (Iwama et al. 2019. PubMed ID: 30842224). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jan 10, 2019)
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no assertion criteria provided
Method: literature only
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MEGA-CORPUS-CALLOSUM SYNDROME WITH CEREBELLAR HYPOPLASIA AND CORTICAL MALFORMATIONS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000864196.1
First in ClinVar: Jan 14, 2019 Last updated: Jan 14, 2019 |
Comment on evidence:
In 3 unrelated girls (patients 4, 5, and 6) with mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCHCM; 618273), Tripathy et al. (2018) identified … (more)
In 3 unrelated girls (patients 4, 5, and 6) with mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCHCM; 618273), Tripathy et al. (2018) identified a de novo heterozygous c.1549G-A transition in the MAST1 gene, resulting in a gly517-to-ser (G517S) substitution at a conserved residue in the kinase domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional studies showed that the variant only slightly increased the interaction of MAST1 with microtubules. (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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Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE. | Seo GH | Clinical genetics | 2020 | PMID: 32901917 |
Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations. | Tripathy R | Neuron | 2018 | PMID: 30449657 |
Text-mined citations for rs1568413207 ...
HelpRecord last updated Mar 17, 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.