ClinVar Genomic variation as it relates to human health
NM_021971.4(GMPPB):c.1000G>A (p.Asp334Asn)
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.
Pathogenic(6); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_021971.4(GMPPB):c.1000G>A (p.Asp334Asn)
Variation ID: 60540 Accession: VCV000060540.38
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p21.31 3: 49721835 (GRCh38) [ NCBI UCSC ] 3: 49759268 (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 May 28, 2018 Feb 28, 2024 Nov 28, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_021971.4:c.1000G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_068806.2:p.Asp334Asn missense NM_013334.2:c.1081G>A NM_013334.4:c.1081G>A NP_037466.3:p.Asp361Asn missense NC_000003.12:g.49721835C>T NC_000003.11:g.49759268C>T NG_011603.1:g.37279C>T NG_033731.1:g.7140G>A NG_033731.2:g.7140G>A Q9Y5P6:p.Asp334Asn - Protein change
- D334N, D361N
- Other names
- -
- Canonical SPDI
- NC_000003.12:49721834:C:T
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00007
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. |
|||
GMPPB | - | - |
GRCh38 GRCh37 |
343 | 386 |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 14, 2017 | RCV000054433.11 | |
Uncertain significance (2) |
criteria provided, single submitter
|
- | RCV000054432.6 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2023 | RCV000651273.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 28, 2023 | RCV000788090.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2021 | RCV001836725.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 31, 2020 | RCV002513710.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 10, 2023 | RCV003398643.1 |
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
(Nov 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2T
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001429989.1
First in ClinVar: Aug 22, 2020 Last updated: Aug 22, 2020 |
Clinical Features:
Elevated circulating creatine kinase concentration (present) , Delayed speech and language development (present) , Autism (present) , Hypotonia (present) , High palate (present)
Sex: male
Tissue: blood
|
|
Likely pathogenic
(Dec 31, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003709698.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.1081G>A (p.D361N) alteration is located in exon 8 (coding exon 8) of the GMPPB gene. This alteration results from a G to A substitution … (more)
The c.1081G>A (p.D361N) alteration is located in exon 8 (coding exon 8) of the GMPPB gene. This alteration results from a G to A substitution at nucleotide position 1081, causing the aspartic acid (D) at amino acid position 361 to be replaced by an asparagine (N). Based on data from the Genome Aggregation Database (gnomAD) database, the GMPPB c.1081G>A alteration was observed in 0.01% (19/251044) of total alleles studied, with a frequency of 0.06% (19/30616) in the South Asian subpopulation. This alteration has been reported in conjunction with a second disease-causing allele in multiple patients with congenital/early-onset muscular dystrophy and intellectual disability (Stevens, 2013; Belaya, 2015; Sarkozy, 2018). This amino acid position is highly conserved in available vertebrate species. Functional analysis revealed that this alteration causes the protein to localize differently and aggregate as compared to wild-type protein (Carss, 2013). Additionally, analysis of patient fibroblasts revealed a reduction in glycosylated alpha-dystroglycan (Stevens, 2013). The p.D361N alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Oct 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001796948.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: abnormal subcellular localization (Carss et al., 2013); In silico analysis supports that this missense variant has a deleterious … (more)
Published functional studies demonstrate a damaging effect: abnormal subcellular localization (Carss et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26133662, 28456886, 23768512, 29437916, 23894383, 33060286) (less)
|
|
Pathogenic
(Oct 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
GMPPB-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122701.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: GMPPB c.1081G>A (p.Asp361Asn), also referred to as c.1000G>A (p.Asp334Asn) in the literature, results in a conservative amino acid change in the encoded protein … (more)
Variant summary: GMPPB c.1081G>A (p.Asp361Asn), also referred to as c.1000G>A (p.Asp334Asn) in the literature, results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251044 control chromosomes, found exclusively within the South Asian subpopulation at a frequency of 0.00062 in the gnomAD database. c.1081G>A has been reported in the literature as a compound heterozygous genotype in at least two individuals affected with congenital muscular dystrophy who have subsequently been cited in other publications (e.g. Carrs_2013, Stevens_2013, Belaya_2015) and in the homozygous state in 12 individuals from 7 different families in which the variant segregated with a limb-girdle muscular dystrophy-congenital myasthenic syndrome (LGMD/CMS) phenotype (Polavarapu_2021). In all cases, the affected individuals were of South Asian descent, and it has been suggested the variant may be a common founder variant in individuals of South Indian ancestry (Polavarapu_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant formed aggregates in the cytoplasm, whereas the wild type GMPPB protein is soluble, however, this study did not evalute the impact of the variant on enzyme activity (e.g. Carrs_2013). The following publications have been ascertained in the context of this evaluation (PMID: 26133662, 23768512, 34333724, 23894383). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Nov 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024858.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jul 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2T
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000773124.4
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 334 of the GMPPB protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 334 of the GMPPB protein (p.Asp334Asn). This variant is present in population databases (rs397509422, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of GMPPB-related conditions (PMID: 23768512, 26133662; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 60540). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GMPPB function (PMID: 23768512). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormality of the musculature
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV000927088.1
First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022 |
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002053816.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2T
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047145.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.1000G>A (p.Asp334Asn) in GMPPB gene has been reported in the homozygous state in an individual affected myopathy and it has been observed … (more)
The missense variant c.1000G>A (p.Asp334Asn) in GMPPB gene has been reported in the homozygous state in an individual affected myopathy and it has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with congenital muscular dystrophy(Carss KJ et.al.,2013). Experimental studies have shown that this missense change disrupts the normal cellular localization of GDP-mannose pyrophorphorylase and leads to a reduction of glycosylated alpha-dystroglycan(Stevens E et.al.,2013). The p.Asp334Asn variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.007568% is reported in gnomAD. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic. The amino acid Asp at position 334 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asp334Asn in GMPPB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . (less)
Clinical Features:
Muscular dystrophy (present) , Fatigable weakness (present) , Intellectual disability (present) , Seizure (present)
|
|
Pathogenic
(Jul 11, 2013)
|
no assertion criteria provided
Method: literature only
|
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 14
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000082909.3
First in ClinVar: Aug 08, 2013 Last updated: Sep 28, 2018 |
Comment on evidence:
In a patient (P1) with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A14 (MDDGA14; 615350), Carss et al. (2013) identified compound heterozygous mutations … (more)
In a patient (P1) with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A14 (MDDGA14; 615350), Carss et al. (2013) identified compound heterozygous mutations in the GMPPB gene: a c.1000G-A transition resulting in an asp334-to-asn (D334N) substitution at a highly conserved residue at the C terminus, and a c.220C-T transition resulting in an arg74-to-ter (R74X; 615320.0002) substitution. The mutations were identified by exome sequencing and confirmed by Sanger sequencing. Each unaffected parent was heterozygous for 1 of the mutations. Transfection of the D334N mutation into myoblasts caused the protein to form cytoplasmic aggregates. The R74X mutation, which occurs in the nucleotidyl transferase domain, is predicted to cause a severely truncated protein and nonsense-mediated mRNA. The patient had severely delayed psychomotor development, sensorineural hearing loss, retinal dysfunction, and pontine and cerebellar hypoplasia on brain MRI. Studies of the patient's skeletal muscle and fibroblasts showed decreased glycosylation of alpha-dystroglycan (DAG1; 128239), which was partially restored by transfection of wildtype GMPPB. An unrelated patient (P2) with a somewhat less severe phenotype, limb-girdle muscular dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352) with mental retardation, was found to be compound heterozygous for D334N and a c.64C-T transition resulting in a pro22-to-ser (P22S; 615320.0003) substitution at a highly conserved residue in the nucleotidyl transferase domain. Transfection of the P22S mutation into myoblasts caused the protein to aggregate near membrane protrusions into the cytoplasm. (less)
|
|
Pathogenic
(Jul 11, 2013)
|
no assertion criteria provided
Method: literature only
|
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000082910.3
First in ClinVar: Aug 08, 2013 Last updated: Sep 28, 2018 |
Comment on evidence:
In a patient (P1) with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A14 (MDDGA14; 615350), Carss et al. (2013) identified compound heterozygous mutations … (more)
In a patient (P1) with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A14 (MDDGA14; 615350), Carss et al. (2013) identified compound heterozygous mutations in the GMPPB gene: a c.1000G-A transition resulting in an asp334-to-asn (D334N) substitution at a highly conserved residue at the C terminus, and a c.220C-T transition resulting in an arg74-to-ter (R74X; 615320.0002) substitution. The mutations were identified by exome sequencing and confirmed by Sanger sequencing. Each unaffected parent was heterozygous for 1 of the mutations. Transfection of the D334N mutation into myoblasts caused the protein to form cytoplasmic aggregates. The R74X mutation, which occurs in the nucleotidyl transferase domain, is predicted to cause a severely truncated protein and nonsense-mediated mRNA. The patient had severely delayed psychomotor development, sensorineural hearing loss, retinal dysfunction, and pontine and cerebellar hypoplasia on brain MRI. Studies of the patient's skeletal muscle and fibroblasts showed decreased glycosylation of alpha-dystroglycan (DAG1; 128239), which was partially restored by transfection of wildtype GMPPB. An unrelated patient (P2) with a somewhat less severe phenotype, limb-girdle muscular dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352) with mental retardation, was found to be compound heterozygous for D334N and a c.64C-T transition resulting in a pro22-to-ser (P22S; 615320.0003) substitution at a highly conserved residue in the nucleotidyl transferase domain. Transfection of the P22S mutation into myoblasts caused the protein to aggregate near membrane protrusions into the cytoplasm. (less)
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
A founder mutation in the GMPPB gene [c.1000G > A (p.Asp334Asn)] causes a mild form of limb-girdle muscular dystrophy/congenital myasthenic syndrome (LGMD/CMS) in South Indian patients. | Polavarapu K | Neurogenetics | 2021 | PMID: 34333724 |
Mobility shift of beta-dystroglycan as a marker of GMPPB gene-related muscular dystrophy. | Sarkozy A | Journal of neurology, neurosurgery, and psychiatry | 2018 | PMID: 29437916 |
Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies. | Belaya K | Brain : a journal of neurology | 2015 | PMID: 26133662 |
Flow cytometry for the analysis of α-dystroglycan glycosylation in fibroblasts from patients with dystroglycanopathies. | Stevens E | PloS one | 2013 | PMID: 23894383 |
Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan. | Carss KJ | American journal of human genetics | 2013 | PMID: 23768512 |
Text-mined citations for rs397509422 ...
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.