ClinVar Genomic variation as it relates to human health
NM_000352.6(ABCC8):c.3640C>T (p.Arg1214Trp)
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.3640C>T (p.Arg1214Trp)
Variation ID: 235633 Accession: VCV000235633.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.1 11: 17402671 (GRCh38) [ NCBI UCSC ] 11: 17424218 (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 Jun 9, 2016 Feb 20, 2024 Jan 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000352.6:c.3640C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000343.2:p.Arg1214Trp missense NM_001287174.3:c.3643C>T NP_001274103.1:p.Arg1215Trp missense NM_001351295.2:c.3706C>T NP_001338224.1:p.Arg1236Trp missense NM_001351296.2:c.3640C>T NP_001338225.1:p.Arg1214Trp missense NM_001351297.2:c.3637C>T NP_001338226.1:p.Arg1213Trp missense NR_147094.2:n.3789C>T non-coding transcript variant NC_000011.10:g.17402671G>A NC_000011.9:g.17424218G>A NG_008867.1:g.79232C>T LRG_790:g.79232C>T LRG_790t1:c.3640C>T LRG_790p1:p.Arg1214Trp LRG_790t2:c.3643C>T LRG_790p2:p.Arg1215Trp Q09428:p.Arg1214Trp - Protein change
- R1214W, R1215W, R1213W, R1236W
- Other names
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- Canonical SPDI
- NC_000011.10:17402670: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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 |
2299 | 2424 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000223959.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 12, 2017 | RCV000588494.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 21, 2017 | RCV000666191.1 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 13, 2020 | RCV001828097.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 29, 2023 | RCV003469115.1 |
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
(Aug 27, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281360.2
First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016 |
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Pathogenic
(Jan 12, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial hyperinsulinism
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696589.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The ABCC8 c.3640C>T (p.Arg1214Trp also known as p.Arg1215Trp) variant located in the ABC transporter type 1, transmembrane domain (via InterPro) causes a missense … (more)
Variant summary: The ABCC8 c.3640C>T (p.Arg1214Trp also known as p.Arg1215Trp) variant located in the ABC transporter type 1, transmembrane domain (via InterPro) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 8/121412 (1/15174), which does not exceed the estimated maximal expected allele frequency for a pathogenic ABCC8 variant of 1/298. Multiple publications cite the variant in affected individuals, who are compound heterozygotes. In addition, multiple clinical diagnostic laboratory classifies this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Likely pathogenic
(Mar 21, 2017)
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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: SCV000790442.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Oct 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: SCV004197151.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 24, 2024)
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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: SCV001219153.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1214 of the ABCC8 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1214 of the ABCC8 protein (p.Arg1214Trp). This variant is present in population databases (rs139964066, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive congenital hyperinsulinemia (PMID: 17575084, 23275527, 24401662, 24937539, 26180531, 28442472). This variant is also known as p.Arg1215Trp. ClinVar contains an entry for this variant (Variation ID: 235633). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg1214 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14692646, 15562009, 20685672, 23275527). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 13, 2020)
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no assertion criteria provided
Method: clinical testing
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Hereditary hyperinsulinism
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002075583.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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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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Functional and Metabolomic Consequences of K(ATP) Channel Inactivation in Human Islets. | Li C | Diabetes | 2017 | PMID: 28442472 |
Genetic characteristics and long-term follow-up of 11 patients with congenital hyperinsulinism followed in a single center. | Warncke K | Journal of pediatric endocrinology & metabolism : JPEM | 2016 | PMID: 27682711 |
A novel case of compound heterozygous congenital hyperinsulinism without high insulin levels. | Brady C | International journal of pediatric endocrinology | 2015 | PMID: 26180531 |
Sulfonylurea in the treatment of neonatal diabetes mellitus children with heterogeneous genetic backgrounds. | Zhang M | Journal of pediatric endocrinology & metabolism : JPEM | 2015 | PMID: 25781672 |
Long-term follow-up of children with congenital hyperinsulinism on octreotide therapy. | Demirbilek H | The Journal of clinical endocrinology and metabolism | 2014 | PMID: 24937539 |
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 |
Characterization of the ABCC8 gene mutation and phenotype in patients with congenital hyperinsulinism in western Saudi Arabia. | Al-Agha AE | Saudi medical journal | 2013 | PMID: 24145932 |
Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. | Ellard S | Diabetologia | 2013 | PMID: 23771172 |
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 |
ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism. | Bellanné-Chantelot C | Journal of medical genetics | 2010 | PMID: 20685672 |
Congenital hyperinsulinism associated ABCC8 mutations that cause defective trafficking of ATP-sensitive K+ channels: identification and rescue. | Yan FF | Diabetes | 2007 | PMID: 17575084 |
Prenatal diagnosis and postnatal management of diffuse congenital hyperinsulinism: a case report. | Peranteau WH | Fetal diagnosis and therapy | 2006 | PMID: 16969006 |
Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes. | Henwood MJ | The Journal of clinical endocrinology and metabolism | 2005 | PMID: 15562009 |
Preoperative evaluation of infants with focal or diffuse congenital hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation. | Stanley CA | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 14715863 |
Histopathology of congenital hyperinsulinism: retrospective study with genotype correlations. | Suchi M | Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society | 2003 | PMID: 14692646 |
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Text-mined citations for rs139964066 ...
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.