ClinVar Genomic variation as it relates to human health
NM_005787.6(ALG3):c.512G>A (p.Arg171Gln)
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_005787.6(ALG3):c.512G>A (p.Arg171Gln)
Variation ID: 2129 Accession: VCV000002129.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q27.1 3: 184245291 (GRCh38) [ NCBI UCSC ] 3: 183963079 (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 Apr 21, 2017 Apr 6, 2024 Mar 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005787.6:c.512G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005778.1:p.Arg171Gln missense NM_001006941.2:c.368G>A NP_001006942.1:p.Arg123Gln missense NM_005787.5:c.512G>A NR_024533.1:n.443G>A non-coding transcript variant NR_024534.1:n.506G>A non-coding transcript variant NC_000003.12:g.184245291C>T NC_000003.11:g.183963079C>T NG_008924.2:g.9222G>A Q92685:p.Arg171Gln - Protein change
- R171Q, R123Q
- Other names
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- Canonical SPDI
- NC_000003.12:184245290:C:T
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00005
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 | ||
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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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ALG3 | - | - |
GRCh38 GRCh37 |
197 | 245 |
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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Mar 17, 2024 | RCV000002211.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 13, 2023 | RCV002512673.1 |
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
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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 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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ALG3-congenital disorder of glycosylation
Affected status: yes
Allele origin:
biparental
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921929.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Id (MIM#601110). … (more)
0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Id (MIM#601110). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (9 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ALG3 domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed in multiple homozygous individuals and a single compound heterozygous individual with congenital disorder of glycosylation (LOVD, PMID: 15840742, PMID: 33583022, PMID: 28742265, PMID: 18679822). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregated in seven homozygous, affected siblings (PMID: 28742265). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic, by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely pathogenic
(Jan 13, 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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GeneDx
Accession: SCV003195124.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
Published functional studies suggest that this variant, in the homozygous state, results in impaired lipid-linked oligosaccharides (Sun et al., 2005); In silico analysis supports that … (more)
Published functional studies suggest that this variant, in the homozygous state, results in impaired lipid-linked oligosaccharides (Sun et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 33583022, 28742265, 15840742, 18679822, 34645488) (less)
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Likely pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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ALG3-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804943.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jul 01, 2005)
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no assertion criteria provided
Method: literature only
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CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Id
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022369.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017 |
Comment on evidence:
In a patient with a severe phenotype of congenital disorder of glycosylation type Id (CDG1D; 601110), Sun et al. (2005) detected homozygosity for a G-to-A … (more)
In a patient with a severe phenotype of congenital disorder of glycosylation type Id (CDG1D; 601110), Sun et al. (2005) detected homozygosity for a G-to-A transition at nucleotide 512 in exon 4 of the ALG3 gene, resulting in an arg171-to-gln (R171Q) substitution. The patient, whose parents were from the Dominican Republic, died at 19 days of age. Hyperinsulinemic hypoglycemia was present, and autopsy revealed islet cell hyperplasia with increased beta-cell mass. Other features were Dandy-Walker malformation, facial dysmorphism, and profound hypotonia. Sun et al. (2005) noted that hyperinsulinemic hypoglycemia had not previously been reported in CDG Id. Lentiviral complementation with wildtype ALG3 corrected the biochemical defect in the patient's fibroblasts. Sun et al. (2005) stated that a substantial portion of both patient and control mRNA transcripts contained the 37-bp deletion (601110.0002). (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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ALG3-congenital disorder of glycosylation
Affected status: yes
Allele origin:
inherited
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001761967.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
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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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Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG. | Alsharhan H | Journal of inherited metabolic disease | 2021 | PMID: 33583022 |
Congenital disorder of glycosylation id presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia. | Sun L | The Journal of clinical endocrinology and metabolism | 2005 | PMID: 15840742 |
Text-mined citations for rs119103236 ...
HelpRecord last updated Apr 06, 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.