ClinVar Genomic variation as it relates to human health
NM_005271.5(GLUD1):c.965G>A (p.Arg322His)
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_005271.5(GLUD1):c.965G>A (p.Arg322His)
Variation ID: 16129 Accession: VCV000016129.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.2 10: 87061009 (GRCh38) [ NCBI UCSC ] 10: 88820766 (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 4, 2013 Apr 15, 2024 Jun 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005271.5:c.965G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005262.1:p.Arg322His missense NM_001318900.1:c.566G>A NP_001305829.1:p.Arg189His missense NM_001318901.1:c.464G>A NP_001305830.1:p.Arg155His missense NM_001318902.1:c.464G>A NP_001305831.1:p.Arg155His missense NM_001318904.2:c.464G>A NP_001305833.1:p.Arg155His missense NM_001318905.2:c.464G>A NP_001305834.1:p.Arg155His missense NM_001318906.2:c.464G>A NP_001305835.1:p.Arg155His missense NC_000010.11:g.87061009C>T NC_000010.10:g.88820766C>T NG_013010.1:g.39011G>A P00367:p.Arg322His - Protein change
- R322H, R155H, R189H
- Other names
- R269H
- Canonical SPDI
- NC_000010.11:87061008: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.
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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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GLUD1 | - | - |
GRCh38 GRCh37 |
173 | 275 |
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
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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Jun 23, 2023 | RCV000017509.40 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2020 | RCV001091338.17 |
Submissions - Germline
Classification
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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
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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
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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
(Mar 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hyperinsulinism-hyperammonemia syndrome
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000595006.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Likely pathogenic
(Jun 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hyperinsulinism-hyperammonemia syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV003936070.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
A heterozygous variation in exon 7 of the GLUD1 gene that results in the amino acid substitution of Histidine for arginine at codon 322 was … (more)
A heterozygous variation in exon 7 of the GLUD1 gene that results in the amino acid substitution of Histidine for arginine at codon 322 was detected. The observed variant c.965G>A (p.Arg322His) has not been reported in the 1000 genomes databases. The in silico prediction of the variant are possibly damaging by LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. (less)
Age: 30-39 years
Sex: male
Method: Sanger sequencing using custom designed primers that targeted exonic regions of the GLUD1 gene.
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Pathogenic
(Dec 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hyperinsulinism-hyperammonemia syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000933885.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein … (more)
This variant is not present in population databases (gnomAD no frequency). 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 GLUD1 protein function. ClinVar contains an entry for this variant (Variation ID: 16129). This variant is also known as R269H. This missense change has been observed in individual(s) with hyperinsulinism hyperammonemia syndrome (PMID: 11214910, 27188453, 30306091). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 322 of the GLUD1 protein (p.Arg322His). (less)
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Pathogenic
(Jan 01, 2020)
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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: SCV001247306.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 01, 2001)
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no assertion criteria provided
Method: literature only
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HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 6
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037781.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 9 affected members of 6 unrelated families with hyperinsulinemic hypoglycemia and hyperammonemia (606762), Santer et al. (2001) identified heterozygosity for a 978G-A transition in … (more)
In 9 affected members of 6 unrelated families with hyperinsulinemic hypoglycemia and hyperammonemia (606762), Santer et al. (2001) identified heterozygosity for a 978G-A transition in exon 7 of the GLUD1 gene, resulting in an arg269-to-his (R269H) substitution within the catalytic domain. (less)
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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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Clinical and Molecular Spectrum of Glutamate Dehydrogenase Gene Defects in 26 Chinese Congenital Hyperinsulinemia Patients. | Su C | Journal of diabetes research | 2018 | PMID: 30306091 |
Clinical and genetic characterization of congenital hyperinsulinism in Spain. | Martínez R | European journal of endocrinology | 2016 | PMID: 27188453 |
Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome. | Santer R | Human genetics | 2001 | PMID: 11214910 |
Text-mined citations for rs121909737 ...
HelpRecord last updated Apr 15, 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.