NM_000352.6(ABCC8):c.1333-1013A>G AND Hyperinsulinemic hypoglycemia, familial, 1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Nov 8, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000032668.8

Allele description [Variation Report for NM_000352.6(ABCC8):c.1333-1013A>G]

NM_000352.6(ABCC8):c.1333-1013A>G

Gene:

ABCC8:ATP binding cassette subfamily C member 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.1

Genomic location:

Preferred name:

NM_000352.6(ABCC8):c.1333-1013A>G

HGVS:

NC_000011.10:g.17444325T>C
NG_008867.1:g.37578A>G
NM_000352.6:c.1333-1013A>GMANE SELECT
NM_001287174.3:c.1333-1013A>G
NM_001351295.2:c.1333-1013A>G
NM_001351296.2:c.1330-1013A>G
NM_001351297.2:c.1330-1013A>G
LRG_790t1:c.1333-1013A>G
LRG_790t2:c.1333-1013A>G
LRG_790:g.37578A>G
NC_000011.9:g.17465872T>C
NM_000352.3:c.1333-1013A>G
NM_000352.4:c.1333-1013A>G

Nucleotide change:

IVS8, A-G, -1013

Links:

OMIM: 600509.0029; dbSNP: rs980458021

NCBI 1000 Genomes Browser:

rs980458021

Molecular consequence:

NM_000352.6:c.1333-1013A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001287174.3:c.1333-1013A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001351295.2:c.1333-1013A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001351296.2:c.1330-1013A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001351297.2:c.1330-1013A>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Hyperinsulinemic hypoglycemia, familial, 1 (HHF1)
Synonyms:: HYPERINSULINISM, FAMILIAL, WITH PANCREATIC NESIDIOBLASTOSIS; HYPOGLYCEMIA, HYPERINSULINEMIC, OF INFANCY; NESIDIOBLASTOSIS OF PANCREAS; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009734; MedGen: C2931832; Orphanet: 276575; Orphanet: 276598; OMIM: 256450

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000056431	OMIM	no assertion criteria provided	Pathogenic (Jan 10, 2013)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002060016	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Nov 8, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32928245, 23273570 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000056431

OMIM

no assertion criteria provided

Pathogenic
(Jan 10, 2013)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002060016

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))

Likely pathogenic
(Nov 8, 2021)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Diagnosis of congenital Hyperinsulinism can occur not only in infancy but also in later age: a new flow chart from a single center experience.

Casertano A, De Matteis A, Mozzillo E, Rosanio FM, Buono P, Fattorusso V, Franzese A.

Ital J Pediatr. 2020 Sep 14;46(1):131. doi: 10.1186/s13052-020-00894-5.

PubMed [citation]

PMID:: 32928245
PMCID:: PMC7490857

Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation.

Flanagan SE, Xie W, Caswell R, Damhuis A, Vianey-Saban C, Akcay T, Darendeliler F, Bas F, Guven A, Siklar Z, Ocal G, Berberoglu M, Murphy N, O'Sullivan M, Green A, Clayton PE, Banerjee I, Clayton PT, Hussain K, Weedon MN, Ellard S.

Am J Hum Genet. 2013 Jan 10;92(1):131-6. doi: 10.1016/j.ajhg.2012.11.017. Epub 2012 Dec 27.

PubMed [citation]

PMID:: 23273570
PMCID:: PMC3542457

Details of each submission

From OMIM, SCV000056431.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 5 probands with diazoxide-unresponsive hypoglycemia due to focal hyperinsulinism (HHF1; 256450), Flanagan et al. (2013) identified heterozygosity for a c.1333-1013A-G transition (c.1333-1013A-G, NM_000352.3) deep within intron 8 of the ABCC8 gene, creating a cryptic splice donor site that results in the inclusion of an out-of-frame 76-bp pseudoexon and premature termination. The mutation was inherited from the father in 4 of the patients; in the fifth patient, the mutation was not found in the mother but no DNA was available from the father. The variant was also identified in homozygosity in 1 patient with diffuse hyperinsulinism diagnosed on postmortem examination, and was present in heterozygosity in both parents. Chromosome 11 microsatellite analysis revealed a shared haplotype among the 6 patients, 4 of whom were from Ireland, suggesting that the variant represents a founder mutation in the Irish population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV002060016.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

NM_000352.3(ABCC8):c.1333-1013A>G is an intronic variant classified as likely pathogenic in the context of familial hyperinsulinism, ABCC8-related. c.1333-1013A>G has been observed in cases with relevant disease (PMID: 23273570, 32928245). Functional assessments of this variant are available in the literature (PMID: 23273570). c.1333-1013A>G has not been observed in population frequency databases. In summary, NM_000352.3(ABCC8):c.1333-1013A>G is an intronic variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2025

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