ClinVar Genomic variation as it relates to human health
NM_000352.6(ABCC8):c.2521C>T (p.Arg841Ter)
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.
Pathogenic(4); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000352.6(ABCC8):c.2521C>T (p.Arg841Ter)
Variation ID: 996301 Accession: VCV000996301.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.1 11: 17412701 (GRCh38) [ NCBI UCSC ] 11: 17434248 (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 Feb 12, 2021 Feb 14, 2024 Aug 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000352.6:c.2521C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000343.2:p.Arg841Ter nonsense NM_001287174.3:c.2524C>T NP_001274103.1:p.Arg842Ter nonsense NM_001351295.2:c.2587C>T NP_001338224.1:p.Arg863Ter nonsense NM_001351296.2:c.2521C>T NP_001338225.1:p.Arg841Ter nonsense NM_001351297.2:c.2518C>T NP_001338226.1:p.Arg840Ter nonsense NR_147094.2:n.2590C>T non-coding transcript variant NC_000011.10:g.17412701G>A NC_000011.9:g.17434248G>A NG_008867.1:g.69202C>T LRG_790:g.69202C>T LRG_790t1:c.2521C>T LRG_790p1:p.Arg841Ter LRG_790t2:c.2524C>T LRG_790p2:p.Arg842Ter - Protein change
- R840*, R841*, R842*, R863*
- Other names
- NM_000352.6(ABCC8):c.2521C>T
- p.Arg841Ter
- Canonical SPDI
- NC_000011.10:17412700: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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
- Links
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 |
2305 | 2431 |
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 (1) |
criteria provided, single submitter
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Jan 23, 2021 | RCV001290673.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV002245949.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV002245950.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 13, 2023 | RCV001859230.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2023 | RCV003321823.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 24, 2022 | RCV003469507.1 |
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
(Jan 23, 2021)
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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: SCV001478804.1
First in ClinVar: Feb 12, 2021 Last updated: Feb 12, 2021 |
Comment:
Variant summary: ABCC8 c.2521C>T (p.Arg841X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ABCC8 c.2521C>T (p.Arg841X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.1e-06 in 247456 control chromosomes. c.2521C>T has been reported in the literature in individuals affected with Congenital Hyperinsulinism and in carriers sequenced in control databases (example, Brunetti-Pierri_2008, Mohnike_2014, Salomon-Estebanez_2016, Craigie_2018, Bonnefond_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Uncertain significance
(-)
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criteria provided, single submitter
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
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Transitory neonatal diabetes mellitus
(Somatic mutation)
Affected status: unknown
Allele origin:
somatic
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002515471.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to … (more)
Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs1484689392) in neonatal diabetes yet. (less)
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Uncertain significance
(-)
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criteria provided, single submitter
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
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Maturity onset diabetes mellitus in young
(Somatic mutation)
Affected status: unknown
Allele origin:
somatic
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002515473.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to … (more)
Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs1484689392) in MODY yet. (less)
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Pathogenic
(Aug 16, 2023)
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criteria provided, single submitter
Method: curation
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Hyperinsulinemic hypoglycemia, familial, 1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV004026540.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
The p.Arg841Ter variant in ABCC8 has been reported in 6 individuals with hyperinsulinemic hypoglycemia (PMID: 18988933, 30386300, 24401662, 34927408, 27908292, 35475025), and has been identified … (more)
The p.Arg841Ter variant in ABCC8 has been reported in 6 individuals with hyperinsulinemic hypoglycemia (PMID: 18988933, 30386300, 24401662, 34927408, 27908292, 35475025), and has been identified in 0.005% (1/18266) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1484689392). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 96301) and has been interpreted as pathogenic by Invitae and Women's Health and Genetics/Laboratory Corporation of America (LabCorp). Of the 6 affected individuals, one of those was a homozygote, which increases the likelihood that the p.Arg841Ter variant is pathogenic (PMID: 34927408). This nonsense variant leads to a premature termination codon at position 841, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_supporting, PM2_supporting, PVS1 (Richards 2015). (less)
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Pathogenic
(Dec 24, 2022)
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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: SCV004209191.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 13, 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: SCV002229297.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 996301). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 996301). This variant is also known as p.Arg842Ter . This premature translational stop signal has been observed in individual(s) with ABCC8-related conditions (PMID: 18988933, 34927408). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg841*) in the ABCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197). (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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Investigating Genetic Mutations in a Large Cohort of Iranian Patients with Congenital Hyperinsulinism. | Razzaghy-Azar M | Journal of clinical research in pediatric endocrinology | 2022 | PMID: 34927408 |
Pathogenic variants in actionable MODY genes are associated with type 2 diabetes. | Bonnefond A | Nature metabolism | 2020 | PMID: 33046911 |
Molecular and clinical characteristics of monogenic diabetes mellitus in southern Chinese children with onset before 3 years of age. | Lin Y | BMJ open diabetes research & care | 2020 | PMID: 32792356 |
Update of variants identified in the pancreatic β-cell K(ATP) channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes. | De Franco E | Human mutation | 2020 | PMID: 32027066 |
Clinical Diversity in Focal Congenital Hyperinsulinism in Infancy Correlates With Histological Heterogeneity of Islet Cell Lesions. | Craigie RJ | Frontiers in endocrinology | 2018 | PMID: 30386300 |
Conservatively treated Congenital Hyperinsulinism (CHI) due to K-ATP channel gene mutations: reducing severity over time. | Salomon-Estebanez M | Orphanet journal of rare diseases | 2016 | PMID: 27908292 |
ABCC8-Related Maturity-Onset Diabetes of the Young (MODY12): Clinical Features and Treatment Perspective. | Ovsyannikova AK | Diabetes therapy : research, treatment and education of diabetes and related disorders | 2016 | PMID: 27538677 |
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 |
Heterozygous ABCC8 mutations are a cause of MODY. | Bowman P | Diabetologia | 2012 | PMID: 21989597 |
ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism. | Bellanné-Chantelot C | Journal of medical genetics | 2010 | PMID: 20685672 |
Case report: pathological features of aberrant pancreatic development in congenital hyperinsulinism due to ABCC8 mutations. | Brunetti-Pierri N | Annals of clinical and laboratory science | 2008 | PMID: 18988933 |
Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations. | Rafiq M | Diabetes care | 2008 | PMID: 18025408 |
Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. | Babenko AP | The New England journal of medicine | 2006 | PMID: 16885549 |
A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. | Proks P | Human molecular genetics | 2006 | PMID: 16613899 |
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Text-mined citations for rs1484689392 ...
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.