ClinVar Genomic variation as it relates to human health
NM_000352.6(ABCC8):c.1562G>A (p.Arg521Gln)
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.1562G>A (p.Arg521Gln)
Variation ID: 157683 Accession: VCV000157683.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.1 11: 17442788 (GRCh38) [ NCBI UCSC ] 11: 17464335 (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 Nov 23, 2014 Dec 17, 2023 Jun 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000352.6:c.1562G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000343.2:p.Arg521Gln missense NM_001287174.3:c.1562G>A NP_001274103.1:p.Arg521Gln missense NM_001351295.2:c.1562G>A NP_001338224.1:p.Arg521Gln missense NM_001351296.2:c.1559G>A NP_001338225.1:p.Arg520Gln missense NM_001351297.2:c.1559G>A NP_001338226.1:p.Arg520Gln missense NR_147094.2:n.1628G>A non-coding transcript variant NC_000011.10:g.17442788C>T NC_000011.9:g.17464335C>T NG_008867.1:g.39115G>A LRG_790:g.39115G>A LRG_790t1:c.1562G>A LRG_790p1:p.Arg521Gln LRG_790t2:c.1562G>A LRG_790p2:p.Arg521Gln - Protein change
- R521Q, R520Q
- Other names
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- Canonical SPDI
- NC_000011.10:17442787: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.
Exome Aggregation Consortium (ExAC) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00010
The Genome Aggregation Database (gnomAD) 0.00011
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Trans-Omics for Precision Medicine (TOPMed) 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 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Jul 12, 2013 | RCV000144978.10 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Nov 2, 2023 | RCV000722048.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 17, 2021 | RCV001262624.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 28, 2023 | RCV002298483.6 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 15, 2022 | RCV002505120.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 13, 2022 | RCV003447502.1 |
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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Uncertain significance
(Jul 12, 2013)
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criteria provided, single submitter
Method: clinical testing
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Diabetes mellitus
(Autosomal unknown)
Affected status: unknown
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000192014.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Uncertain significance
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Type 2 diabetes mellitus
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440561.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Comment:
This variant was identified as compound heterozygous.
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Uncertain significance
(Nov 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Type 2 diabetes mellitus
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579575.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: male
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Uncertain significance
(Aug 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV002817243.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
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Uncertain significance
(Jun 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598615.2
First in ClinVar: Nov 05, 2022 Last updated: Jul 29, 2023 |
Comment:
Variant summary: ABCC8 c.1562G>A (p.Arg521Gln) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded … (more)
Variant summary: ABCC8 c.1562G>A (p.Arg521Gln) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251160 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than predicted for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (0.0001 vs 0.0034), allowing no conclusion about variant significance. c.1562G>A has been reported in the literature in individuals affected with Hyperinsulinism without a family history for Congenital Hyperinsulinism (example: Calabria_2012, and Snider_2013). One publication listed this variant as medically actionable - likely pathogenic for AD hyperinsulinemia (Rego_2018), however, recent publications evaluated it as VUS (example: Franco_2019 and Maron_2021). In addition, co-occurrences with other pathogenic variant (HNF1A c.160C>T, p.Arg54X) has been reported in a male patient diagnosed with Maturity Onset Diabetes Of The Young (Ivanoshchuk_2021). These reports do not provide unequivocal conclusions about association of the variant with Congenital Hyperinsulinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23275527, 22855730, 30487145, 32027066, 33587123, 33477506). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS: n=3; Likely pathogenic: n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Mar 15, 2022)
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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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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026002.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Uncertain significance
(Dec 13, 2022)
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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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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175695.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The ABCC8 c.1562G>A variant is classified as VUS (PM1) The ABCC8 c.1562G>A variant is a single nucleotide change in exon 10/39 of the ABCC8 gene, … (more)
The ABCC8 c.1562G>A variant is classified as VUS (PM1) The ABCC8 c.1562G>A variant is a single nucleotide change in exon 10/39 of the ABCC8 gene, which is predicted to change the amino acid arginine at position 521 in the protein to glutamine. This variant is located in the conserved ABC-membrane domain (PM1). The variant has been reported in dbSNP (rs368114790), in population databases (gnomAD 17/152162, 0 homs) and in the HGMD database as disease causing (CM1212138). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 157683). The variant has been reported in teh scientific literature in patients with hyperinsulinism and as a variant of uncertain significance (PMID:21378087, 22855730, 23275527, 3202066). (less)
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Likely pathogenic
(Jan 01, 2017)
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Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Familial hyperinsulinism
Affected status: unknown
Allele origin:
germline
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Snyder Lab, Genetics Department, Stanford University
Accession: SCV000853091.1
First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018 |
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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 |
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Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study. | Maron JL | JAMA pediatrics | 2021 | PMID: 33587123 |
The Mutation Spectrum of Maturity Onset Diabetes of the Young (MODY)-Associated Genes among Western Siberia Patients. | Ivanoshchuk DE | Journal of personalized medicine | 2021 | PMID: 33477506 |
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 |
High-frequency actionable pathogenic exome variants in an average-risk cohort. | Rego S | Cold Spring Harbor molecular case studies | 2018 | PMID: 30487145 |
Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. | Snider KE | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 23275527 |
GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism owing to inactivating mutations in the ATP-sensitive K+ channel. | Calabria AC | Diabetes | 2012 | PMID: 22855730 |
The contribution of rapid KATP channel gene mutation analysis to the clinical management of children with congenital hyperinsulinism. | Banerjee I | European journal of endocrinology | 2011 | PMID: 21378087 |
The use of a testosterone intravaginal device to detect oestrus in goats. | Del Campo CH | Acta veterinaria Scandinavica. Supplementum | 1988 | PMID: 3202066 |
Text-mined citations for rs368114790 ...
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.