ClinVar Genomic variation as it relates to human health
NM_000352.6(ABCC8):c.2473C>T (p.Arg825Trp)
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_000352.6(ABCC8):c.2473C>T (p.Arg825Trp)
Variation ID: 1338472 Accession: VCV001338472.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.1 11: 17413396 (GRCh38) [ NCBI UCSC ] 11: 17434943 (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 Jan 29, 2022 Feb 14, 2024 Jun 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000352.6:c.2473C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000343.2:p.Arg825Trp missense NM_001287174.3:c.2476C>T NP_001274103.1:p.Arg826Trp missense NM_001351295.2:c.2539C>T NP_001338224.1:p.Arg847Trp missense NM_001351296.2:c.2473C>T NP_001338225.1:p.Arg825Trp missense NM_001351297.2:c.2470C>T NP_001338226.1:p.Arg824Trp missense NR_147094.2:n.2542C>T non-coding transcript variant NC_000011.10:g.17413396G>A NC_000011.9:g.17434943G>A NG_008867.1:g.68507C>T NG_054084.1:g.527G>A LRG_790:g.68507C>T LRG_790t1:c.2473C>T LRG_790p1:p.Arg825Trp LRG_790t2:c.2476C>T LRG_790p2:p.Arg826Trp - Protein change
- R824W, R825W, R826W, R847W
- Other names
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- Canonical SPDI
- NC_000011.10:17413395:G:A
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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.
Exome Aggregation Consortium (ExAC) 0.00001
- Links
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
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. |
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ABCC8 | - | - |
GRCh38 GRCh37 |
2309 | 2435 | |
LOC110121471 | - | - | - | GRCh38 | - | 97 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Jun 29, 2023 | RCV001817843.8 |
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
(Aug 06, 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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Genetic Services Laboratory, University of Chicago
Accession: SCV002069315.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.2473C>T, in exon 20 that results in an amino acid change, p.Arg825Trp. This sequence … (more)
DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.2473C>T, in exon 20 that results in an amino acid change, p.Arg825Trp. This sequence change has been described in the gnomAD database in one heterozygous individual (dbSNP rs779736828). The p.Arg825Trp change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is known to be functional. The p.Arg825Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Arg825Trp amino acid change has been described in the heterozygous state in several patients with transient neonatal diabetes (PMIDs: 17446535, 29527407, 17389331, 27167055, 24622368, and 19021632). Functional studies demonstrated that the p.Arg825Trp variant causes an increase in KATP current, thereby reducing insulin secretion and accounting for the diabetes of patients carrying the p.Arg825Trp variant (PMID: 18497752). (less)
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Pathogenic
(Nov 23, 2022)
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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: SCV002757266.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Comment:
Published in vitro functional studies measuring ATPase activity demonstrate a slower deactivation of the potassium channels compared to wildtype, suggesting that downstream effects lead to … (more)
Published in vitro functional studies measuring ATPase activity demonstrate a slower deactivation of the potassium channels compared to wildtype, suggesting that downstream effects lead to less insulin secretion (de Wet el al., 2008); 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: 27167055, 29112131, 24622368, 27849623, 29527407, 22210575, 24825091, 17446535, 26839896, 28993341, 17389331, 31595705, 29207974, 18497752, 18436707, 32418263, 34566892) (less)
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Pathogenic
(Jun 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002143364.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
Experimental studies have shown that this missense change affects ABCC8 function (PMID: 18497752). An algorithm developed to predict the effect of missense changes on protein … (more)
Experimental studies have shown that this missense change affects ABCC8 function (PMID: 18497752). 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. ClinVar contains an entry for this variant (Variation ID: 1338472). This variant is also known as p.R826W. This missense change has been observed in individual(s) with autosomal dominant and autosomal recessive neonatal diabetes mellitus (PMID: 17446535, 18497752, 24622368, 24825091, 26839896, 27849623, 29527407). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs779736828, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 825 of the ABCC8 protein (p.Arg825Trp). For these reasons, this variant has been classified as Pathogenic. (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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Transient Neonatal Diabetes Mellitus in a Very Preterm Infant due to ABCC8 Mutation. | Piccini B | AJP reports | 2018 | PMID: 29527407 |
Successful transition to sulfonylurea therapy in two Iraqi siblings with neonatal diabetes mellitus and iDEND syndrome due to ABCC8 mutation. | Ozsu E | Journal of pediatric endocrinology & metabolism : JPEM | 2016 | PMID: 27849623 |
Genetic Analysis and Follow-Up of 25 Neonatal Diabetes Mellitus Patients in China. | Cao B | Journal of diabetes research | 2016 | PMID: 26839896 |
Permanent neonatal diabetes mellitus in Jordan. | Abujbara MA | Journal of pediatric endocrinology & metabolism : JPEM | 2014 | PMID: 24825091 |
Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study [corrected]. | Busiah K | The lancet. Diabetes & endocrinology | 2013 | PMID: 24622368 |
A mutation (R826W) in nucleotide-binding domain 1 of ABCC8 reduces ATPase activity and causes transient neonatal diabetes. | de Wet H | EMBO reports | 2008 | PMID: 18497752 |
Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. | Flanagan SE | Diabetes | 2007 | PMID: 17446535 |
Text-mined citations for rs779736828 ...
HelpRecord last updated Feb 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.