ClinVar Genomic variation as it relates to human health
NM_001244710.2(GFPT1):c.331C>T (p.Arg111Cys)
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
-
NM_001244710.2(GFPT1):c.331C>T (p.Arg111Cys)
Variation ID: 29735 Accession: VCV000029735.36
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p13.3 2: 69363563 (GRCh38) [ NCBI UCSC ] 2: 69590695 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Aug 22, 2016 May 12, 2024 May 15, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001244710.2:c.331C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001231639.1:p.Arg111Cys missense NM_002056.4:c.331C>T NP_002047.2:p.Arg111Cys missense NC_000002.12:g.69363563G>A NC_000002.11:g.69590695G>A NG_029542.1:g.28688C>T LRG_787:g.28688C>T LRG_787t1:c.331C>T LRG_787p1:p.Arg111Cys Q06210:p.Arg111Cys - Protein change
- R111C
- Other names
- -
- Canonical SPDI
- NC_000002.12:69363562:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00014
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00029
The Genome Aggregation Database (gnomAD) 0.00030
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. |
|||
GFPT1 | - | - |
GRCh38 GRCh37 |
551 | 566 |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
May 15, 2023 | RCV000022587.42 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 1, 2019 | RCV001090973.17 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Mar 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myasthenic syndrome 12
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915920.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The GFPT1 c.331C>T (p.Arg111Cys) missense variant has been reported in two studies and identified in nine individuals with congenital myasthenic syndrome, including in six homozygotes … (more)
The GFPT1 c.331C>T (p.Arg111Cys) missense variant has been reported in two studies and identified in nine individuals with congenital myasthenic syndrome, including in six homozygotes and in three compound heterozygotes, from four unrelated families (Senderek et al. 2011; Bauche et al. 2017). Segregation data from the families was consistent with autosomal recessive inheritance. The p.Arg111Cys variant was absent from at least 240 controls but is reported at a frequency of 0.000566 in the Latino population of the Genome Aggregation Database. In addition, Bauche et al. (2017) identified four unrelated affected individuals that carried a different amino acid change at the same residue (p.Arg111His) in a compound heterozygous state, suggesting that the Arg111 codon may be a mutational hot spot. Based on the evidence, the p.Arg111Cys variant is classified as likely pathogenic for congenital myasthenic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
Likely pathogenic
(Aug 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246776.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
|
|
Likely pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myasthenic syndrome 12
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841848.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). Missense changes are a common disease-causing mechanism. … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.70; 3Cnet: 0.62). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029735). A different missense change at the same codon (p.Arg111His) has been reported to be associated with GFPT1 related disorder (ClinVar ID: VCV001073321). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Muscular dystrophy (present) , Hypotonia (present)
|
|
Pathogenic
(May 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myasthenic syndrome 12
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000964958.7
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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 GFPT1 protein function. ClinVar contains an entry for this variant (Variation ID: 29735). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 21310273, 23794683, 28712002). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs201322234, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 111 of the GFPT1 protein (p.Arg111Cys). (less)
|
|
Pathogenic
(Feb 11, 2011)
|
no assertion criteria provided
Method: literature only
|
MYASTHENIC SYNDROME, CONGENITAL, 12
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000043876.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In affected members of a large consanguineous Libyan family with autosomal recessive congenital myasthenic syndrome-12 (CMS12; 610542) with tubular aggregates reported by Sieb et al. … (more)
In affected members of a large consanguineous Libyan family with autosomal recessive congenital myasthenic syndrome-12 (CMS12; 610542) with tubular aggregates reported by Sieb et al. (1996), Senderek et al. (2011) identified a homozygous c.331C-T transition in exon 4 of the GFPT1 gene, resulting in an arg111-to-cys (R111C) substitution. A Swedish family with the disorder was found to be compound heterozygous for R111C and a 1-bp insertion in exon 4 (222insA; 138292.0002), which resulted in a frameshift (Gln76fs). The mutations were not observed in 240 and 117 controls, respectively. In vitro functional expression studies in HEK293 cells indicated that the R111C mutation did not result in decreased enzyme activity, but studies of patient muscle biopsies and cultured muscle cells with other GFPT1 mutations showed reduced amounts of the GFPT1 protein, suggesting increased turnover or defective translation. (less)
|
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 |
---|---|---|---|---|
Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy. | Bauché S | Journal of neurology | 2017 | PMID: 28712002 |
GFPT1-myasthenia: clinical, structural, and electrophysiologic heterogeneity. | Selcen D | Neurology | 2013 | PMID: 23794683 |
Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. | Senderek J | American journal of human genetics | 2011 | PMID: 21310273 |
An autosomal-recessive congenital myasthenic syndrome with tubular aggregates in a Libyan family. | Sieb JP | Neuromuscular disorders : NMD | 1996 | PMID: 8664562 |
Text-mined citations for rs201322234 ...
HelpRecord last updated May 12, 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.