ClinVar Genomic variation as it relates to human health
NM_000352.6(ABCC8):c.4432G>A (p.Gly1478Arg)
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.4432G>A (p.Gly1478Arg)
Variation ID: 434045 Accession: VCV000434045.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.1 11: 17394379 (GRCh38) [ NCBI UCSC ] 11: 17415926 (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 Aug 28, 2017 Feb 14, 2024 Aug 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000352.6:c.4432G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000343.2:p.Gly1478Arg missense NM_001287174.3:c.4435G>A NP_001274103.1:p.Gly1479Arg missense NM_001351295.2:c.4498G>A NP_001338224.1:p.Gly1500Arg missense NM_001351296.2:c.4432G>A NP_001338225.1:p.Gly1478Arg missense NM_001351297.2:c.4429G>A NP_001338226.1:p.Gly1477Arg missense NR_147094.2:n.4727G>A non-coding transcript variant NC_000011.10:g.17394379C>T NC_000011.9:g.17415926C>T NG_008867.1:g.87524G>A LRG_790:g.87524G>A LRG_790t1:c.4432G>A LRG_790p1:p.Gly1478Arg LRG_790t2:c.4435G>A LRG_790p2:p.Gly1479Arg - Protein change
- G1478R, G1479R, G1477R, G1500R
- Other names
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- Canonical SPDI
- NC_000011.10:17394378: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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
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. |
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ABCC8 | - | - |
GRCh38 GRCh37 |
2309 | 2435 |
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. |
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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2018 | RCV000503504.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763232.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 9, 2023 | RCV000710389.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 29, 2023 | RCV003470623.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 1, 2019 | RCV001848864.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 25, 2023 | RCV003330733.1 |
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. |
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Pathogenic
(Jul 21, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hyperinsulinemic hypoglycemia, familial, 1
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000592979.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Likely pathogenic
(Feb 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hyperinsulinemic hypoglycemia, familial, 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000797781.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Pathogenic
(Jun 25, 2018)
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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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Athena Diagnostics
Accession: SCV000840599.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
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Likely pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Type 2 diabetes mellitus
Leucine-induced hypoglycemia Hyperinsulinemic hypoglycemia, familial, 1 Permanent neonatal diabetes mellitus 1 Diabetes mellitus, transient neonatal, 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893865.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Aug 09, 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: SCV001582811.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic … (more)
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1478 of the ABCC8 protein (p.Gly1478Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital hyperinsulinism and autosomal dominant ABCC8-related early onset diabetes (PMID: 19475716, 30098243, 30977832, 32928245). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 434045). 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 ABCC8 protein function. (less)
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Pathogenic
(Jul 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant hyperinsulinism due to SUR1 deficiency
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV002104247.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
Comment:
This is a recurrent variant that has been previously reported in individuals with congenital hyperinsulinism, albeit with variable expressivity and incomplete penetrance (PMID: 18596924, 19475716, … (more)
This is a recurrent variant that has been previously reported in individuals with congenital hyperinsulinism, albeit with variable expressivity and incomplete penetrance (PMID: 18596924, 19475716, 8650576, 23275527, 24401662).There are reports of both familial transmission of this variant (PMID: 18596924) and a sporadic case where the p.Gly1478Arg change occurred de novo (PMID: 19475716). The p.Gly1478Arg change falls within the second nucleotide-binding domain (NBD2) where MgADP binds (UniProtKB - Q09428). This variant has been experimentally demonstrated to impair responsiveness to channel agonists such as diazoxide and MgADP (PMID: 18596924). This variant has not been observed in large population cohorts (absent from >282,800 alleles tested; GnomAD v2.1). (less)
Clinical Features:
Large for gestational age (present)
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Pathogenic
(Aug 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hyperinsulinemic hypoglycemia, familial, 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004039404.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: ABCC8 c.4432G>A (p.Gly1478Arg) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. … (more)
Variant summary: ABCC8 c.4432G>A (p.Gly1478Arg) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251454 control chromosomes (gnomAD). c.4432G>A has been reported in the literature in multiple individuals affected with Dominant CH (e.g. Nichols_1996, Pinney_2008, Sandal_2009, Kapoor_2013), including at least one case of de novo inheritance (Sandal_2009), and it has been shown to segregate with the disease phenotype within family members, although with incomplete penetrance (Pinney_2008). 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 resulted in diminished channel response to MgADP and diazoxide (Pinney_2008). The following publications have been ascertained in the context of this evaluation (PMID: 23345197, 8650576, 18596924, 19475716). 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)
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Pathogenic
(Aug 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Type 2 diabetes mellitus
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004193216.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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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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Diagnosis of congenital Hyperinsulinism can occur not only in infancy but also in later age: a new flow chart from a single center experience. | Casertano A | Italian journal of pediatrics | 2020 | PMID: 32928245 |
Identifying Pathogenic Variants of Monogenic Diabetes Using Targeted Panel Sequencing in an East Asian Population. | Park SS | The Journal of clinical endocrinology and metabolism | 2019 | PMID: 30977832 |
[Clinical features and genetic analysis of seven patients with congenital hyperinsulinism]. | Zhang Y | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2018 | PMID: 30098243 |
Clinical and genetic evaluation of patients with KATP channel mutations from the German registry for congenital hyperinsulinism. | Mohnike K | Hormone research in paediatrics | 2014 | PMID: 24401662 |
Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. | Kapoor RR | European journal of endocrinology | 2013 | PMID: 23345197 |
Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. | Snider KE | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 23275527 |
Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations. | Kapoor RR | Diabetologia | 2011 | PMID: 21674179 |
Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains. | Kelly L | Protein science : a publication of the Protein Society | 2010 | PMID: 20799350 |
The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy. | Sandal T | Clinical genetics | 2009 | PMID: 19475716 |
Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. | Pinney SE | The Journal of clinical investigation | 2008 | PMID: 18596924 |
Insight in eukaryotic ABC transporter function by mutation analysis. | Frelet A | FEBS letters | 2006 | PMID: 16442101 |
Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy. | Shyng SL | Diabetes | 1998 | PMID: 9648840 |
Regulation of KATP channel activity by diazoxide and MgADP. Distinct functions of the two nucleotide binding folds of the sulfonylurea receptor. | Shyng S | The Journal of general physiology | 1997 | PMID: 9382893 |
Adenosine diphosphate as an intracellular regulator of insulin secretion. | Nichols CG | Science (New York, N.Y.) | 1996 | PMID: 8650576 |
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Text-mined citations for rs72559715 ...
HelpRecord last updated May 12, 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.