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NM_000352.6(ABCC8):c.1630+1G>T AND Hyperinsulinemic hypoglycemia, familial, 1

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Aug 16, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000411351.5

Allele description [Variation Report for NM_000352.6(ABCC8):c.1630+1G>T]

NM_000352.6(ABCC8):c.1630+1G>T

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.1630+1G>T
HGVS:
  • NC_000011.10:g.17442719C>A
  • NG_008867.1:g.39184G>T
  • NM_000352.6:c.1630+1G>TMANE SELECT
  • NM_001287174.3:c.1630+1G>T
  • NM_001351295.2:c.1630+1G>T
  • NM_001351296.2:c.1627+1G>T
  • NM_001351297.2:c.1627+1G>T
  • LRG_790t1:c.1630+1G>T
  • LRG_790t2:c.1630+1G>T
  • LRG_790:g.39184G>T
  • NC_000011.9:g.17464266C>A
  • NM_000352.3:c.1630+1G>T
  • NM_000352.4:c.1630+1G>T
  • NM_000352.5:c.1630+1G>T
Links:
dbSNP: rs773306994
NCBI 1000 Genomes Browser:
rs773306994
Molecular consequence:
  • NM_000352.6:c.1630+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001287174.3:c.1630+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001351295.2:c.1630+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001351296.2:c.1627+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001351297.2:c.1627+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000485965Counsyl
criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))		Pathogenic
(Mar 10, 2016) 		unknownclinical testing

PubMed (4)
[See all records that cite these PMIDs]

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV004026558Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Aug 16, 2023) 		germlinecuration

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Altered Phenotype of β-Cells and Other Pancreatic Cell Lineages in Patients With Diffuse Congenital Hyperinsulinism in Infancy Caused by Mutations in the ATP-Sensitive K-Channel.

Salisbury RJ, Han B, Jennings RE, Berry AA, Stevens A, Mohamed Z, Sugden SA, De Krijger R, Cross SE, Johnson PP, Newbould M, Cosgrove KE, Hanley KP, Banerjee I, Dunne MJ, Hanley NA.

Diabetes. 2015 Sep;64(9):3182-8. doi: 10.2337/db14-1202. Epub 2015 Apr 30.

PubMed [citation]
PMID:
25931474
PMCID:
PMC4542438

The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy.

Sandal T, Laborie LB, Brusgaard K, Eide SA, Christesen HB, Søvik O, Njølstad PR, Molven A.

Clin Genet. 2009 May;75(5):440-8.

PubMed [citation]
PMID:
19475716
See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000485965.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV004026558.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The c.1630+1G>T variant in ABCC8 has been reported in at least 12 individuals with hyperinsulinemic hypoglycemia (PMID: 20685672, 33688939, 10426386, 27334808, 17236890, 10338089, 9618169, 31997554), and has been identified in 0.005% (1/21648) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs773306994). 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: 370604) and has been interpreted as pathogenic by Counsyl, Invitae, and Natera Inc. Of the 12 affected individuals, 6 were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans, which increases the likelihood that the c.1630+1G>T variant is pathogenic (PMID: 20685672, 33688939, 10426386, 17236890, 9618169). This variant is located in the 3' splice region. SpliceAI predictions indicate use of an out-of-frame cryptic splice site 70 bases from the intron-exon boundary, providing evidence that this variant may cause a frameshift and lead to a premature termination codon downstream. This alteration is then predicted to lead to a truncated or absent protein. However, this information is not predictive enough to determine pathogenicity. 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_very-strong, PM2_supporting, PVS1 (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024