ClinVar Genomic variation as it relates to human health
NM_001244710.2(GFPT1):c.686-2A>G
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_001244710.2(GFPT1):c.686-2A>G
Variation ID: 540353 Accession: VCV000540353.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p13.3 2: 69581446 (GRCh37) [ NCBI UCSC ] 2: 69354314 (GRCh38) [ 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 May 12, 2024 Jan 23, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001244710.2:c.686-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_002056.4:c.685+175A>G intron variant NC_000002.12:g.69354314T>C NC_000002.11:g.69581446T>C NG_029542.1:g.37937A>G LRG_787:g.37937A>G LRG_787t1:c.686-2A>G - Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:69354313:T:C
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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.
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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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GFPT1 | - | - |
GRCh38 GRCh37 |
551 | 566 |
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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Jan 23, 2024 | RCV000650361.21 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001836857.9 | |
GFPT1-related myasthenic syndrome
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Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2022 | RCV002260516.10 |
Pathogenic (1) |
criteria provided, single submitter
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May 12, 2022 | RCV002507119.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2023 | RCV003334001.6 | |
GFPT1-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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May 10, 2023 | RCV003392496.4 |
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
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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
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of the musculature
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV000927078.1
First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022 |
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Pathogenic
(Oct 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Congenital myasthenic syndrome 12
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Pars Genome Lab
Accession: SCV001960986.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Sex: male
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital myasthenic syndrome 12
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058686.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are … (more)
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000540353). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000024, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID:23794683, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Myopathy (present) , Abnormal facial shape (present)
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Pathogenic
(Jan 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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GFPT1-related myasthenic syndrome
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV002540253.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
Comment:
The GFPT1 c.686-2A>G variant results in the substitution of an adenine within the consensus splice acceptor site with a guanine, which may result in splicing … (more)
The GFPT1 c.686-2A>G variant results in the substitution of an adenine within the consensus splice acceptor site with a guanine, which may result in splicing defects. Across a selection of the available literature, this variant has been identified in at least five individuals with a congenital myasthenic syndrome or limb-girdle muscle weakness, including in a confirmed or presumed homozygous state in four individuals, and in a compound heterozygous state in one individual (Selcen et al. 2013; Yis et al. 2017; Natera-de Benito et al. 2017; Gonzalez-Quereda et al. 2020; Töpf et al. 2020). The highest frequency of this allele in the Genome Aggregation Database is 0.000148 in the Latino/Admixed American population (version 2.1.1). This variant precedes the muscle-specific exon of GFPT1, and patient cDNA studies have shown that it eliminates the first four nucleotides of this exon and results in missense changes of 56 amino acids and a premature stop codon (Selcen et al. 2013). This variant was identified in a homozygous state. Based on the available evidence, the c.686-2A>G variant is classified as pathogenic for GFPT1-related myasthenic syndrome. (less)
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Pathogenic
(May 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital myasthenic syndrome 4C
Congenital myasthenic syndrome 12
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002813973.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(May 02, 2023)
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criteria provided, single submitter
Method: curation
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Congenital myasthenic syndrome 12
(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: SCV003922366.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
The homozygous c.686-2A>G variant in GFPT1 was identified by our study in one individual with congenital myasthenic syndrome. The c.686-2A>G variant in GFPT1 has been … (more)
The homozygous c.686-2A>G variant in GFPT1 was identified by our study in one individual with congenital myasthenic syndrome. The c.686-2A>G variant in GFPT1 has been previously reported in at least four unrelated individuals with congenital myasthenic syndrome 12 (PMID: 28464723, PMID: 29054425, PMID: 32403337, PMID: 32528171, PMID: 23794683) but has been identified in 0.015% (5/33776) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs772941684). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 540353) and has been interpreted as pathogenic by Invitae, Illumina, 3billion, Pars Genome Lab, and Kariminejad - Najmabadi Pathology & Genetics Center. Of these four individuals with congenital myasthenic syndrome 12 (PMID: 28464723, PMID: 29054425, PMID: 32403337, PMID: 32528171, PMID: 23794683), three were homozygotes (PMID: 28464723, PMID: 29054425, PMID: 32403337, PMID: 32528171) and one was a compound heterozygote who carried a likely pathogenic variant in trans (PMID: 23794683, ClinVar Variation ID: 859066), which increases the likelihood that the c.686-2A>G variant is pathogenic. RT-PCR and cDNA analysis of patient muscle tissue showed that the c.686-2A>G variant resulted in a 4 base-pair deletion of the muscle-specific exon of GFPT1, leading to frameshift and a premature stop codon 56 amino acids downstream (PMID: 23794683). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the GFPT1 gene is strongly associated to autosomal recessive congenital myasthenic syndrome 12. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital myasthenic syndrome 12. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PS3_Supporting (Richards 2015). (less)
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Pathogenic
(May 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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GFPT1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119360.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The GFPT1 c.686-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the … (more)
The GFPT1 c.686-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with congenital myasthenic syndrome (see for example, Selcen et al. 2013. PubMed ID: 23794683; Yis U et al. 2017. PubMed ID: 28464723; Natera-de Benito et al. 2017. PubMed ID: 29054425). In vitro functional study suggests this variant impacts protein function (Patient 6 in Figure 3, Selcen et al. 2013. PubMed ID: 23794683). This variant is reported in 0.015% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-69581446-T-C). Variants that disrupt the consensus splice acceptor site in GFPT1 are expected to be pathogenic. This variant is interpreted as pathogenic.. (less)
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Pathogenic
(Jun 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital myasthenic syndrome 12
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004236841.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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Congenital myasthenic syndrome 12
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000772204.7
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 8 of the GFPT1 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects an acceptor splice site in intron 8 of the GFPT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with congenital myasthenic syndrome (PMID: 23794683, 28464723, 29054425). ClinVar contains an entry for this variant (Variation ID: 540353). Studies have shown that disruption of this splice site results in deletion of the first 4 nucleotides of the muscle-specific exon of GFPT1 and introduces a premature termination codon (PMID: 23794683). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 2023)
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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: SCV004042075.6
First in ClinVar: Oct 14, 2023 Last updated: May 12, 2024 |
Comment:
GFPT1: PVS1, PM3, PM2:Supporting, PS3:Supporting
Number of individuals with the variant: 1
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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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Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. | Töpf A | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32528171 |
Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain. | Gonzalez-Quereda L | Genes | 2020 | PMID: 32403337 |
Molecular characterization of congenital myasthenic syndromes in Spain. | Natera-de Benito D | Neuromuscular disorders : NMD | 2017 | PMID: 29054425 |
Genetic Landscape of Congenital Myasthenic Syndromes From Turkey: Novel Mutations and Clinical Insights. | Yiş U | Journal of child neurology | 2017 | PMID: 28464723 |
GFPT1-myasthenia: clinical, structural, and electrophysiologic heterogeneity. | Selcen D | Neurology | 2013 | PMID: 23794683 |
Text-mined citations for rs1011196447 ...
HelpRecord last updated Jun 02, 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.