NM_000352.6(ABCC8):c.2506C>T (p.Arg836Ter) AND Hyperinsulinemic hypoglycemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (5 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:: RCV000169276.20

Allele description [Variation Report for NM_000352.6(ABCC8):c.2506C>T (p.Arg836Ter)]

NM_000352.6(ABCC8):c.2506C>T (p.Arg836Ter)

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.2506C>T (p.Arg836Ter)

Other names:

NM_000352.6(ABCC8):c.2506C>T; p.Arg836Ter

HGVS:

NC_000011.10:g.17412716G>A
NG_008867.1:g.69187C>T
NM_000352.6:c.2506C>TMANE SELECT
NM_001287174.1(ABCC8):c.2509C>T
NM_001287174.3:c.2509C>T
NM_001351295.2:c.2572C>T
NM_001351296.2:c.2506C>T
NM_001351297.2:c.2503C>T
NP_000343.2:p.Arg836Ter
NP_001274103.1:p.Arg837Ter
NP_001338224.1:p.Arg858Ter
NP_001338225.1:p.Arg836Ter
NP_001338226.1:p.Arg835Ter
LRG_790t1:c.2506C>T
LRG_790t2:c.2509C>T
LRG_790:g.69187C>T
LRG_790p1:p.Arg836Ter
LRG_790p2:p.Arg837Ter
NC_000011.9:g.17434263G>A
NM_000352.3:c.2506C>T
NM_000352.4:c.2506C>T
NM_000352.5:c.2506C>T
NM_000352.6:c.2506C>T
NM_001287174.1(ABCC8):c.2509C>T
NM_001287174.1:c.2509C>T
NR_147094.2:n.2575C>T
p.ARG836*
p.Arg837*
p.Arg837Ter

Protein change:

R835*

Links:

dbSNP: rs72559722

NCBI 1000 Genomes Browser:

rs72559722

Molecular consequence:

NR_147094.2:n.2575C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000352.6:c.2506C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001287174.3:c.2509C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351295.2:c.2572C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351296.2:c.2506C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351297.2:c.2503C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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
SCV000220582	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Aug 9, 2014)	unknown	literature only	PubMed (5) [See all records that cite these PMIDs] 17378627, 21422196, 23067144, 10204114, 15579781 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000996272	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001361436	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 16, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15579781, 20943781 Citation Link,
SCV001422873	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 16, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV002072037	Genetic Services Laboratory, University of Chicago	no assertion criteria provided	Pathogenic (Jun 21, 2021)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Genotype-phenotype associations in patients with severe hyperinsulinism of infancy.

Greer RM, Shah J, Jeske YW, Brown D, Walker RM, Cowley D, Bowling FG, Liaskou D, Harris M, Thomsett MJ, Choong C, Bell JR, Jack MM, Cotterill AM.

Pediatr Dev Pathol. 2007 Jan-Feb;10(1):25-34.

PubMed [citation]

PMID:: 17378627

Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism.

Park SE, Flanagan SE, Hussain K, Ellard S, Shin CH, Yang SW.

Eur J Endocrinol. 2011 Jun;164(6):919-26. doi: 10.1530/EJE-11-0160. Epub 2011 Mar 21. Erratum in: Eur J Endocrinol. 2011 Sep;165(3):485-6.

PubMed [citation]

PMID:: 21422196

See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000220582.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (5)

#	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

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000996272.1

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

Description

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.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361436.1

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

Description

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.

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422873.4

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

Description

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).

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

From Genetic Services Laboratory, University of Chicago, SCV002072037.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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).

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

Last Updated: May 7, 2024

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