ClinVar Genomic variation as it relates to human health
NM_000352.6(ABCC8):c.2506C>T (p.Arg836Ter)
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
-
NM_000352.6(ABCC8):c.2506C>T (p.Arg836Ter)
Variation ID: 188915 Accession: VCV000188915.42
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.1 11: 17412716 (GRCh38) [ NCBI UCSC ] 11: 17434263 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 29, 2015 Feb 20, 2024 Jan 28, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000352.6:c.2506C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000343.2:p.Arg836Ter nonsense NM_001287174.3:c.2509C>T NP_001274103.1:p.Arg837Ter nonsense NM_001351295.2:c.2572C>T NP_001338224.1:p.Arg858Ter nonsense NM_001351296.2:c.2506C>T NP_001338225.1:p.Arg836Ter nonsense NM_001351297.2:c.2503C>T NP_001338226.1:p.Arg835Ter nonsense NR_147094.2:n.2575C>T non-coding transcript variant NC_000011.10:g.17412716G>A NC_000011.9:g.17434263G>A NG_008867.1:g.69187C>T LRG_790:g.69187C>T LRG_790t1:c.2506C>T LRG_790p1:p.Arg836Ter LRG_790t2:c.2509C>T LRG_790p2:p.Arg837Ter - Protein change
- R836*, R837*, R835*, R858*
- Other names
- NM_000352.6(ABCC8):c.2506C>T
- p.Arg836Ter
- Canonical SPDI
- NC_000011.10:17412715:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00008
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 | ||
---|---|---|---|---|---|---|
HI score
Help
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. |
|||
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Aug 16, 2023 | RCV000169276.20 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 28, 2024 | RCV000201895.17 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2020 | RCV000763234.9 | |
Pathogenic (1) |
no assertion criteria provided
|
Sep 16, 2020 | RCV001277195.6 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
|
Jan 2, 2024 | RCV002243837.7 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
|
Jan 2, 2024 | RCV002243836.7 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 10, 2023 | RCV003462267.1 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Jun 24, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics Inc
Accession: SCV000612205.1
First in ClinVar: Nov 15, 2015 Last updated: Nov 15, 2015 |
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893867.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(Dec 16, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperinsulinemic hypoglycemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361436.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: ABCC8 c.2506C>T (p.Arg836X) 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.2506C>T (p.Arg836X) 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 6.1e-05 in 246774 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (6.1e-05 vs 0.0034). c.2506C>T has been reported in the literature, in compound heterozygous and homozygous state, in individuals affected with Congenital Hyperinsulinism (Tornovsky_2004, Yorifuji_2011). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant severely impacts trafficking of the channel to the plasma membrane (it did not reach the plasma membrane at all), which in turn causes a substantial defect in channel activity (Tornovsky_2004). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Apr 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperinsulinemic hypoglycemia, familial, 1
Leucine-induced hypoglycemia Type 2 diabetes mellitus Permanent neonatal diabetes mellitus 1 Diabetes mellitus, transient neonatal, 2
Affected status: no
Allele origin:
germline
|
Elsea Laboratory, Baylor College of Medicine
Accession: SCV001424286.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
Sex: female
Testing laboratory: Org: 1006
|
|
Pathogenic
(Nov 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002015476.2
First in ClinVar: Nov 20, 2021 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also known as c.2509C>T p.(R837*); This variant is associated with the following publications: (PMID: 17378627, 20943781, 23067144, 26379717, 29644095, 24332968, 10923633, 25555642, 25525159, 23301914, 2563966, 23345197, 25765446, 10204114, 15579781, 21422196, 21968108, 25639667, 26740944, 28701683, 31019026) (less)
|
|
Pathogenic
(Aug 16, 2023)
|
criteria provided, single submitter
Method: curation
|
Hyperinsulinemic hypoglycemia, familial, 1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422873.4
First in ClinVar: Jul 19, 2020 Last updated: Aug 19, 2023 |
Comment:
The p.Arg836Ter variant in ABCC8 has been reported in at least 11 individuals with congenital hyperinsulinism (PMID: 30386300, 26740944, 17378627, 26379717, 28701683, 23345197, 25765446, 23301914, … (more)
The p.Arg836Ter variant in ABCC8 has been reported in at least 11 individuals with congenital hyperinsulinism (PMID: 30386300, 26740944, 17378627, 26379717, 28701683, 23345197, 25765446, 23301914, 21422196), and has been identified in 0.03% (12/35140) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs72559722). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (VariationID: 188915) as pathogenic or likely pathogenic by 11 submitters. Of the 11 affected individuals, 1 of those was a homozygote and 5 were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans or with unknown phase, which increases the likelihood that the p.Arg836Ter variant is pathogenic (Variation ID: 188864, 939498; PMID: 26740944, 26379717, 28701683, 23345197, 25765446, 21422196). In vitro functional studies provide some evidence that the p.Arg836Ter variant may slightly impact protein function (PMID: 15579781). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 836, 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: PVS1, PM3_very-strong, PS3_supporting (Richards 2015). (less)
|
|
Pathogenic
(Oct 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Type 2 diabetes mellitus
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004197797.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001231207.6
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg836*) in the ABCC8 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg836*) 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). This variant is present in population databases (rs72559722, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with congenital hyperinsulinism (PMID: 23067144, 23301914, 23345197, 26379717, 29644095). This variant is also known as c.2509C>T, p.Arg837X. ClinVar contains an entry for this variant (Variation ID: 188915). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Mar 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996272.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
This nonsense variant is predicted to result in loss of normal protein function. The variant has been previously reported in ClinVar as likely pathogenic (Variation … (more)
This nonsense variant is predicted to result in loss of normal protein function. The variant has been previously reported in ClinVar as likely pathogenic (Variation ID: 188915). This variant has been described in the heterozygous, compound heterozygous, and homozygous state in diffuse and focal congenital hyperinsulinism (PMID: 23067144, 23345197, 23301914, 26379717, 29644095). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.00006 (17/272624) and thus is presumed to be rare. The c.2506C>T (p.Arg836Ter) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2506C>T (p.Arg836Ter) variant is classified as pathogenic. (less)
Number of individuals with the variant: 1
|
|
Likely pathogenic
(Aug 09, 2014)
|
criteria provided, single submitter
Method: literature only
|
Persistent hyperinsulinemic hypoglycemia of infancy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220582.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
Pathogenic
(Oct 07, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000256810.1
First in ClinVar: Nov 15, 2015 Last updated: Nov 15, 2015 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary hyperinsulinism
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001464093.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
Pathogenic
(Jun 21, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Hyperinsulinemic hypoglycemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002072037.3
First in ClinVar: Jan 29, 2022 Last updated: Dec 11, 2022 |
Comment:
DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.2506C>T, which results in the creation of a premature stop codon at amino acid … (more)
DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.2506C>T, which results in the creation of a premature stop codon at amino acid position 836, p.Arg836*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ABCC8 protein with potentially abnormal function. This pathogenic sequence change has previously been described in a patients with both diffuse and focal ABCC8-related hyperinsulinism (PMIDs: 15579781,26379717, 25765446). Functional studies have also demonstrated that this sequence change may impact protein function (PMID: 15579781). (less)
|
|
Uncertain significance
(-)
|
Flagged submission
flagged submission
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Maturity onset diabetes mellitus in young
(Somatic mutation)
Affected status: unknown
Allele origin:
somatic
|
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002515474.1
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 ( rs72559722) in MODY yet. (less)
|
|
Uncertain significance
(-)
|
Flagged submission
flagged submission
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Transitory neonatal diabetes mellitus
(Somatic mutation)
Affected status: unknown
Allele origin:
somatic
|
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002515475.1
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 ( rs72559722) in neonatal diabetes yet. (less)
|
|
click to load more click to collapse | |||||
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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 |
---|---|---|---|---|
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 |
Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. | Farnaes L | NPJ genomic medicine | 2018 | PMID: 29644095 |
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 |
Uncovering the molecular pathogenesis of congenital hyperinsulinism by panel gene sequencing in 32 Chinese patients. | Fan ZC | Molecular genetics & genomic medicine | 2015 | PMID: 26740944 |
Focal form of congenital hyperinsulinism clearly detectable by contrast-enhanced computed tomography imaging. | Hashimoto Y | International journal of pediatric endocrinology | 2015 | PMID: 26379717 |
Three novel pathogenic mutations in KATP channel genes and somatic imprinting alterations of the 11p15 region in pancreatic tissue in patients with congenital hyperinsulinism. | Lee BH | Hormone research in paediatrics | 2015 | PMID: 25765446 |
Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells. | Tornovsky-Babeay S | Cell metabolism | 2014 | PMID: 24332968 |
Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. | Kapoor RR | European journal of endocrinology | 2013 | PMID: 23345197 |
A dominant ABCC8-related hyperinsulinism: familial case report. Moreira et al. ABCC8-related hyperinsulinism. | Moreira MC | Fetal and pediatric pathology | 2013 | PMID: 23301914 |
Efficacy and safety of long-term, continuous subcutaneous octreotide infusion for patients with different subtypes of KATP-channel hyperinsulinism. | Yorifuji T | Clinical endocrinology | 2013 | PMID: 23067144 |
Heterozygous ABCC8 mutations are a cause of MODY. | Bowman P | Diabetologia | 2012 | PMID: 21989597 |
Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism. | Park SE | European journal of endocrinology | 2011 | PMID: 21422196 |
Molecular and clinical analysis of Japanese patients with persistent congenital hyperinsulinism: predominance of paternally inherited monoallelic mutations in the KATP channel genes. | Yorifuji T | The Journal of clinical endocrinology and metabolism | 2011 | PMID: 20943781 |
ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism. | Bellanné-Chantelot C | Journal of medical genetics | 2010 | PMID: 20685672 |
Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations. | Rafiq M | Diabetes care | 2008 | PMID: 18025408 |
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 |
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 |
Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity. | Tornovsky S | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15579781 |
Molecular biology of adenosine triphosphate-sensitive potassium channels. | Aguilar-Bryan L | Endocrine reviews | 1999 | PMID: 10204114 |
click to load more click to collapse |
Text-mined citations for rs72559722 ...
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.