ClinVar Genomic variation as it relates to human health
NM_013339.4(ALG6):c.998C>T (p.Ala333Val)
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_013339.4(ALG6):c.998C>T (p.Ala333Val)
Variation ID: 5497 Accession: VCV000005497.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p31.3 1: 63419380 (GRCh38) [ NCBI UCSC ] 1: 63885051 (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 Jul 16, 2015 Feb 14, 2024 Dec 18, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_013339.4:c.998C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_037471.2:p.Ala333Val missense NC_000001.11:g.63419380C>T NC_000001.10:g.63885051C>T NG_008925.2:g.56791C>T LRG_1260:g.56791C>T LRG_1260t1:c.998C>T LRG_1260p1:p.Ala333Val - Protein change
- A333V
- Other names
- -
- Canonical SPDI
- NC_000001.11:63419379: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) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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. |
|||
ALG6 | - | - |
GRCh38 GRCh37 |
762 | 795 |
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 (7) |
criteria provided, multiple submitters, no conflicts
|
Dec 18, 2023 | RCV000005832.19 | |
Pathogenic (4) |
criteria provided, single submitter
|
Feb 27, 2022 | RCV001547693.8 | |
Pathogenic (1) |
criteria provided, single submitter
|
Apr 21, 2023 | RCV003407284.4 |
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
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. |
|
---|---|---|---|---|---|
Pathogenic
(Aug 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
ALG6-congenital disorder of glycosylation 1C
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915431.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ALG6 c.998C>T (p.Ala333Val) missense variant is reported to be the most common cause of congenital disorders of glycosylation (CDG) (Drijvers et al. 2010; Ichikawa … (more)
The ALG6 c.998C>T (p.Ala333Val) missense variant is reported to be the most common cause of congenital disorders of glycosylation (CDG) (Drijvers et al. 2010; Ichikawa et al. 2013). Across a selection of the available literature, the p.Ala333Val variant has been reported in a total of eight individuals with CDG, including in four homozygotes, comprised of two sibling pairs who are cousins, and in four unrelated compound heterozygotes. This variant was also identified in a heterozygous state in five unaffected parents of the probands (Imbach et al. 1999; Westphal et al. 2000; Drijvers et al. 2010; Ichikawa et al. 2013; Dercksen et al. 2013). The p.Ala333Val variant was absent from controls but is reported at a frequency of 0.000075 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in yeast with a hypoglycosylation phenotype showed that the p.Ala333Val variant was able to only partially restore glycosylation, whereas glycosylation was fully restored with the wild type protein (Imbach et al. 1999; Westphal et al. 2000). Based on the collective evidence, the p.Ala333Val variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
Pathogenic
(Apr 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
ALG6-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004114863.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ALG6 c.998C>T variant is predicted to result in the amino acid substitution p.Ala333Val. This variant has been reported to be causative for congenital disorder … (more)
The ALG6 c.998C>T variant is predicted to result in the amino acid substitution p.Ala333Val. This variant has been reported to be causative for congenital disorder of glycosylation 1c when present in the homozygous or compound heterozygous state (Imbach et al. 1999. PubMed ID: 10359825; Westphal et al. 2000. PubMed ID: 11106564). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-63885051-C-T). This variant is interpreted as pathogenic. (less)
|
|
Pathogenic
(Jul 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
ALG6-congenital disorder of glycosylation 1C
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000792595.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
Pathogenic
(Dec 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
ALG6-congenital disorder of glycosylation 1C
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894082.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Feb 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001767459.3
First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that the A333V variant severely impairs ALG6 protein function and leads to incomplete CPY glycosylation (Imbach et al., 2000; Westphal et … (more)
Published functional studies demonstrate that the A333V variant severely impairs ALG6 protein function and leads to incomplete CPY glycosylation (Imbach et al., 2000; Westphal et al., 2003); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 23430515, 27287710, 10852543, 12855228, 11106564, 20447155, 10359825, 10914684, 14517965, 23044053, 15771971, 31589614, 33413482, 31991610) (less)
|
|
Pathogenic
(Jul 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
ALG6-congenital disorder of glycosylation 1C
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004197188.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
ALG6-congenital disorder of glycosylation 1C
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001213979.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 333 of the ALG6 protein (p.Ala333Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 333 of the ALG6 protein (p.Ala333Val). This variant is present in population databases (rs121908443, gnomAD 0.006%). This missense change has been observed in individual(s) with ALG6-congenital disorder of glycosylation (CDG-Ic) (PMID: 10359825, 10914684, 11106564, 20447155, 23430515, 27287710). 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. ClinVar contains an entry for this variant (Variation ID: 5497). 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 expected to disrupt ALG6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ALG6 function (PMID: 10359825, 10914684, 11106564). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jun 08, 1999)
|
no assertion criteria provided
Method: literature only
|
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ic
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026014.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2015 |
Comment on evidence:
In 4 unrelated patients with CDG Ic (CDG1C; 603147), Imbach et al. (1999) identified a 998C-T transition that led to an ala333-to-val (A333V) amino acid … (more)
In 4 unrelated patients with CDG Ic (CDG1C; 603147), Imbach et al. (1999) identified a 998C-T transition that led to an ala333-to-val (A333V) amino acid substitution in the human homolog of the yeast ALG6 gene. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957079.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Congenital disorder of glycosylation type 1c
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001456284.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809161.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964941.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
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 |
---|---|---|---|---|
ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies. | Morava E | Journal of inherited metabolic disease | 2016 | PMID: 27287710 |
ALG6-CDG in South Africa: Genotype-Phenotype Description of Five Novel Patients. | Dercksen M | JIMD reports | 2013 | PMID: 23430515 |
Congenital disorder of glycosylation type Ic: report of a Japanese case. | Ichikawa K | Brain & development | 2013 | PMID: 23044053 |
Skeletal dysplasia with brachytelephalangy in a patient with a congenital disorder of glycosylation due to ALG6 gene mutations. | Drijvers JM | Clinical genetics | 2010 | PMID: 20447155 |
[Molecular diagnosis of congenital disorders of glycosylation]. | Vuillaumier-Barrot S | Annales de biologie clinique | 2005 | PMID: 15771971 |
Identification of a frequent variant in ALG6, the cause of Congenital Disorder of Glycosylation-Ic. | Westphal V | Human mutation | 2003 | PMID: 14517965 |
Congenital disorder of glycosylation Ic in patients of Indian origin. | Newell JW | Molecular genetics and metabolism | 2003 | PMID: 12855228 |
Reduced heparan sulfate accumulation in enterocytes contributes to protein-losing enteropathy in a congenital disorder of glycosylation. | Westphal V | The American journal of pathology | 2000 | PMID: 11106564 |
Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic. | Imbach T | Human genetics | 2000 | PMID: 10914684 |
Clinical and biochemical characteristics of congenital disorder of glycosylation type Ic, the first recognized endoplasmic reticulum defect in N-glycan synthesis. | Grünewald S | Annals of neurology | 2000 | PMID: 10852543 |
A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic. | Imbach T | Proceedings of the National Academy of Sciences of the United States of America | 1999 | PMID: 10359825 |
click to load more click to collapse |
Text-mined citations for rs121908443 ...
HelpRecord last updated May 19, 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.