ClinVar Genomic variation as it relates to human health
NM_021942.6(TRAPPC11):c.1287+5G>A
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_021942.6(TRAPPC11):c.1287+5G>A
Variation ID: 60511 Accession: VCV000060511.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q35.1 4: 183684059 (GRCh38) [ NCBI UCSC ] 4: 184605212 (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 Nov 6, 2016 Apr 15, 2024 Dec 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_021942.6(TRAPPC11):c.1287+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_021942.6:c.1287+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_199053.3:c.1287+5G>A intron variant NC_000004.12:g.183684059G>A NC_000004.11:g.184605212G>A NG_033102.1:g.29793G>A - Protein change
- Other names
- IVS12DS, G-A, +5
- Canonical SPDI
- NC_000004.12:183684058:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Variation affecting splicing function of RNA Variation Ontology [VariO:0397]
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
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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TRAPPC11 | - | - |
GRCh38 GRCh37 |
866 | 1052 |
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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 17, 2023 | RCV000054409.22 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 7, 2022 | RCV000414573.23 | |
Pathogenic (1) |
criteria provided, single submitter
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May 29, 2020 | RCV001254697.3 |
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
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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
(Aug 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type R18
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
biparental
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Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV000586713.1
First in ClinVar: Nov 06, 2016 Last updated: Nov 06, 2016 |
Comment:
Variant previously described as pathogenic and as a founder mutation was identified in homozygous tate in a patient with strabismus, mildly elevated CK, moderate ID, … (more)
Variant previously described as pathogenic and as a founder mutation was identified in homozygous tate in a patient with strabismus, mildly elevated CK, moderate ID, movement disorder. Both parent were heterozygous carriers. (less)
Clinical Features:
Intellectual disability (present)
Sex: female
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Pathogenic
(Dec 07, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type R18
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680416.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: female
Tissue: blood
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Likely pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type R18
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893669.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(May 29, 2020)
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criteria provided, single submitter
Method: research
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Muscular dystrophy, limb-girdle, autosomal recessive 23
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001430763.1
First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020 |
Comment:
The c.1287+5G>A variant in TRAPPC11 was identified by our study in 1 individual with limb girdle muscular dystrophy in the compound heterozygous state, along with … (more)
The c.1287+5G>A variant in TRAPPC11 was identified by our study in 1 individual with limb girdle muscular dystrophy in the compound heterozygous state, along with another likely pathogenic variant. The variant in TRAPPC11 has been reported in at least 5 Syrian individuals with limb-girdle muscular dystrophy (PMID: 23830518, 31575891), segregated with disease in 3 affected relatives from 2 families (PMID: 23830518), and has been identified in 0.009% (12/129080) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397509418). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as pathogenic/likely pathogenic by multiple submitters (Variation ID: 60511). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 23830518). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for limb-girdle muscular dystrophy in an autosomal recessive manner based on the predicted impact of the variant and multiple homozygous occurrences in individuals with limb-girdle muscular dystrophy, as well as co-segregations with disease in multiple affected family members in two families. ACMG/AMP Criteria applied: PP1_strong, PM2, PS3_moderate, PP3, PM3 (Richards 2015). (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447224.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present) , Microcephaly (present)
Sex: female
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Pathogenic
(Feb 07, 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: SCV000491339.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate disruption of the Golgi apparatus architecture and impaired the binding ability of TRAPPC11 to TRAPPC2 (Bogershausen et al., 2013); Not observed … (more)
Published functional studies demonstrate disruption of the Golgi apparatus architecture and impaired the binding ability of TRAPPC11 to TRAPPC2 (Bogershausen et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 26322222, 24843229, 23830518, 29158550, 31575891, 32528171, 34426522, 25697177) (less)
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Pathogenic
(Nov 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type R18
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002022412.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type R18
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001221302.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 12 of the TRAPPC11 gene. It does not directly change the encoded amino acid sequence of the TRAPPC11 protein. … (more)
This sequence change falls in intron 12 of the TRAPPC11 gene. It does not directly change the encoded amino acid sequence of the TRAPPC11 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs397509418, gnomAD 0.009%). This variant has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy and/or movement disorder and intellectual disability (PMID: 23830518, 29158550). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 60511). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exons 11-12, but is expected to preserve the integrity of the reading-frame (PMID: 23830518). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 2019)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249262.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 3
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Pathogenic
(Jul 11, 2013)
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no assertion criteria provided
Method: literature only
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MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 18
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000082886.3
First in ClinVar: Aug 04, 2013 Last updated: Sep 28, 2018 |
Comment on evidence:
In affected members of 2 Hutterite families with myopathy, a hyperkinetic muscle disorder, and global developmental delay (see 615356), Bogershausen et al. (2013) identified a … (more)
In affected members of 2 Hutterite families with myopathy, a hyperkinetic muscle disorder, and global developmental delay (see 615356), Bogershausen et al. (2013) identified a homozygous G-to-A transition in intron 12 of the TRAPPC11 gene (c.1287+5G-A), resulting in a splice site site mutation and the generation of 2 abnormal transcripts that contain a large deletion (Ala372_Ser429del) in the foie gras domain, and a truncated protein, respectively. The mutation, which was found by homozygosity mapping and whole-exome sequencing, segregated with the disorder. The mutation was found at a frequency of 7% in control Hutterite populations. Studies of patient cells indicated an intracellular trafficking defect. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808816.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931606.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Variation affecting splicing function of RNA
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Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV000586713.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein. | Milev MP | Scientific reports | 2019 | PMID: 31575891 |
Exome Pool-Seq in neurodevelopmental disorders. | Popp B | European journal of human genetics : EJHG | 2017 | PMID: 29158550 |
Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability. | Bögershausen N | American journal of human genetics | 2013 | PMID: 23830518 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5584e390-d334-455b-adc3-000f923dae87 | - | - | - | - |
Text-mined citations for rs397509418 ...
HelpRecord last updated Apr 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.