ClinVar Genomic variation as it relates to human health
NM_000352.6(ABCC8):c.2176G>A (p.Ala726Thr)
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.
Uncertain significance(6); Benign(1); Likely benign(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.2176G>A (p.Ala726Thr)
Variation ID: 434050 Accession: VCV000434050.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.1 11: 17427095 (GRCh38) [ NCBI UCSC ] 11: 17448642 (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 Aug 28, 2017 Feb 20, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000352.6:c.2176G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000343.2:p.Ala726Thr missense NM_001287174.3:c.2176G>A NP_001274103.1:p.Ala726Thr missense NM_001351295.2:c.2242G>A NP_001338224.1:p.Ala748Thr missense NM_001351296.2:c.2173G>A NP_001338225.1:p.Ala725Thr missense NM_001351297.2:c.2173G>A NP_001338226.1:p.Ala725Thr missense NR_147094.2:n.2242G>A non-coding transcript variant NC_000011.10:g.17427095C>T NC_000011.9:g.17448642C>T NG_008867.1:g.54808G>A LRG_790:g.54808G>A LRG_790t1:c.2176G>A LRG_790p1:p.Ala726Thr LRG_790t2:c.2176G>A LRG_790p2:p.Ala726Thr - Protein change
- A726T, A725T, A748T
- Other names
- -
- Canonical SPDI
- NC_000011.10:17427094: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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0.00080 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00039
Trans-Omics for Precision Medicine (TOPMed) 0.00065
The Genome Aggregation Database (gnomAD) 0.00072
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00080
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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May 6, 2022 | RCV000501008.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763719.5 | |
Benign (1) |
criteria provided, single submitter
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Aug 31, 2017 | RCV001102697.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 31, 2017 | RCV001102698.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 19, 2021 | RCV001102699.10 | |
Uncertain significance (1) |
no assertion criteria provided
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Oct 21, 2020 | RCV001278414.4 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV002056831.12 |
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
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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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
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894603.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Benign
(Aug 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Diabetes mellitus, transient neonatal, 2
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001259382.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
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Uncertain significance
(Aug 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Permanent neonatal diabetes mellitus 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001259383.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Aug 31, 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:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001259384.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely benign
(Jun 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000592986.2
First in ClinVar: Aug 28, 2017 Last updated: Jan 29, 2022 |
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Uncertain significance
(May 06, 2022)
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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: SCV002547982.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: ABCC8 c.2176G>A (p.Ala726Thr) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain of the encoded protein sequence. Four … (more)
Variant summary: ABCC8 c.2176G>A (p.Ala726Thr) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 251224 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism (0.00045 vs 0.0034), allowing no conclusion about variant significance. c.2176G>A has been reported in the literature in individuals affected with Familial Hyperinsulinism or pulmonary arterial hypertension. These reports do not provide unequivocal conclusions about association of the variant with Familial Hyperinsulinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/likely benign n=3, VUS n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Nov 19, 2021)
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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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Myriad Genetics, Inc.
Accession: SCV002060111.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_000352.3(ABCC8):c.2176G>A(A726T) is a missense variant classified as a variant of uncertain significance in the context of familial hyperinsulinism, ABCC8-related. A726T has been observed in cases … (more)
NM_000352.3(ABCC8):c.2176G>A(A726T) is a missense variant classified as a variant of uncertain significance in the context of familial hyperinsulinism, ABCC8-related. A726T has been observed in cases with relevant disease (PMID: 23345197, 24401662, 26758964). Functional assessments of this variant are not available in the literature. A726T has been observed in population frequency databases (gnomAD: NFE 0.08%). In summary, there is insufficient evidence to classify NM_000352.3(ABCC8):c.2176G>A(A726T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
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Uncertain significance
(Aug 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV004025618.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
Identified in additional patients with congenital hyperinsulinism in published literature, however, a second ABCC8 variant was not identified (Banerjee et al., 2011; Kapoor et al., … (more)
Identified in additional patients with congenital hyperinsulinism in published literature, however, a second ABCC8 variant was not identified (Banerjee et al., 2011; Kapoor et al., 2013; Mohnike et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32934261, 24401662, 23345197, 32027066, 21378087, 26758964) (less)
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Likely benign
(Jan 29, 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: SCV002396520.4
First in ClinVar: Apr 08, 2022 Last updated: Feb 20, 2024 |
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Uncertain significance
(Oct 21, 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: SCV001465427.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients. | Lago-Docampo M | Scientific reports | 2020 | PMID: 32934261 |
Clinical and Genetic Characteristics, Management and Long-Term Follow-Up of Turkish Patients with Congenital Hyperinsulinism. | Güven A | Journal of clinical research in pediatric endocrinology | 2016 | PMID: 26758964 |
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 |
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 |
Text-mined citations for rs138687850 ...
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.