ClinVar Genomic variation as it relates to human health
NM_000352.6(ABCC8):c.4258C>T (p.Arg1420Cys)
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.4258C>T (p.Arg1420Cys)
Variation ID: 9095 Accession: VCV000009095.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.1 11: 17395659 (GRCh38) [ NCBI UCSC ] 11: 17417206 (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 Mar 12, 2015 Feb 14, 2024 Jun 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000352.6:c.4258C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000343.2:p.Arg1420Cys missense NM_001287174.3:c.4261C>T NP_001274103.1:p.Arg1421Cys missense NM_001351295.2:c.4324C>T NP_001338224.1:p.Arg1442Cys missense NM_001351296.2:c.4258C>T NP_001338225.1:p.Arg1420Cys missense NM_001351297.2:c.4255C>T NP_001338226.1:p.Arg1419Cys missense NR_147094.2:n.4553C>T non-coding transcript variant NC_000011.10:g.17395659G>A NC_000011.9:g.17417206G>A NG_008867.1:g.86244C>T LRG_790:g.86244C>T LRG_790t1:c.4258C>T LRG_790p1:p.Arg1420Cys LRG_790t2:c.4261C>T LRG_790p2:p.Arg1421Cys - Protein change
- R1421C, R1420C, R1419C, R1442C
- Other names
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- Canonical SPDI
- NC_000011.10:17395658: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.
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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 |
2327 | 2456 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Jan 12, 2019 | RCV000009663.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2023 | RCV001235181.7 | |
Hereditary hyperinsulinism
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Likely pathogenic (1) |
no assertion criteria provided
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Jan 23, 2020 | RCV001831557.1 |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 8, 2023 | RCV003473070.1 |
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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Likely pathogenic
(Mar 08, 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: SCV004204074.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Apr 27, 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: SCV000791010.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Pathogenic
(Jan 12, 2019)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000915514.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ABCC8 c.4258C>T (p.Arg1420Cys) missense variant, also referred to as c.4261C>T, (p.Arg1421Cys), has been reported in at least six studies in which it is found … (more)
The ABCC8 c.4258C>T (p.Arg1420Cys) missense variant, also referred to as c.4261C>T, (p.Arg1421Cys), has been reported in at least six studies in which it is found in a total of seven individuals with congenital hyperinsulinism, including in a homozygous state in three individuals (two of whom are siblings), in a compound heterozygous state in one individual, in a heterozygous state in one individual and in two individuals with unknown zygosity (Verkarre et al. 1998; de Lonlay-Debeney et al. 1999; Tanizawa et al. 2000; Bellanné-Chantelot et al. 2010; Snider et al. 2013; Kappor et al. 2013). The variant was absent from 480 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database. The Arg1420 residue is highly conserved. Matsuo et al. (2000) analyzed the functional effect of the p.Arg1420Cys variant and showed it lowers affinity for ATP and ADP binding and leads to enhanced insulin secretion. Tanizawa et al. (2000) transiently expressed the variant protein in COS-7 cells and showed inhibition of channel formation and function compared to wild type. Based on the collective evidence, the p.Arg1420Cys variant is classified as pathogenic for congenital hyperinsulinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 18, 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:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746732.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 11, 2022 |
Age: 20-29 years
Sex: female
Geographic origin: Iran
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Pathogenic
(Jun 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: SCV001407856.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1420 of the ABCC8 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1420 of the ABCC8 protein (p.Arg1420Cys). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 10615958, 10993895, 26246406). 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. ClinVar contains an entry for this variant (Variation ID: 9095). This variant is also known as p.Arg1421Cys. This missense change has been observed in individuals with clinical features of dyslipidemia and/or familial hyperinsulinemia (PMID: 9769320, 10615958, 17378627, 32041611). (less)
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Pathogenic
(Dec 29, 2000)
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no assertion criteria provided
Method: literature only
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HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029881.3
First in ClinVar: Apr 04, 2013 Last updated: May 04, 2020 |
Comment on evidence:
In a sporadic case of persistent hyperinsulinemic hypoglycemia of infancy (HHF1; 256450) due to focal adenomatous hyperplasia, Verkarre et al. (1998) found a 4261C-T transition … (more)
In a sporadic case of persistent hyperinsulinemic hypoglycemia of infancy (HHF1; 256450) due to focal adenomatous hyperplasia, Verkarre et al. (1998) found a 4261C-T transition in exon 33 of the paternally derived SUR gene, leading to an arg1421-to-cys (R1421C) amino acid substitution. The father was constitutionally heterozygous for the same mutation. This was 1 of 12 cases in which loss of maternal alleles of the 11p15 chromosomal region had been found, limited to the hyperplastic lesions of focal adenomatous hyperplasia. Matsuo et al. (2000) analyzed the functional consequences of the R1421C mutation, which they referred to as R1420C. They showed that the mutation lowers the affinity of the nucleotide-binding fold 2 (NBF2) for ATP and ADP and abolishes the ability of nucleotide binding at NBF2 to stabilize 8-azido-ATP binding at NBF1. In addition, the mutation decreases the expression of potassium-ATP channels, and a smaller current in R1420C-PHHI beta cells leads to enhanced insulin secretion. (less)
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Likely pathogenic
(Jan 23, 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: SCV002077483.1
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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Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. | Dron JS | BMC medical genomics | 2020 | PMID: 32041611 |
ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes. | Baier LJ | Diabetes | 2015 | PMID: 26246406 |
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 |
Genotype-phenotype associations in patients with severe hyperinsulinism of infancy. | Greer RM | Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society | 2007 | PMID: 17378627 |
Potassium channel regulation. | Campbell JD | EMBO reports | 2003 | PMID: 14593442 |
Functional analysis of a mutant sulfonylurea receptor, SUR1-R1420C, that is responsible for persistent hyperinsulinemic hypoglycemia of infancy. | Matsuo M | The Journal of biological chemistry | 2000 | PMID: 10993895 |
Clinical features of 52 neonates with hyperinsulinism. | de Lonlay-Debeney P | The New England journal of medicine | 1999 | PMID: 10202168 |
Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. | Verkarre V | The Journal of clinical investigation | 1998 | PMID: 9769320 |
Text-mined citations for rs28938469 ...
HelpRecord last updated Jun 23, 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.