NM_000352.6(ABCC8):c.239T>G (p.Met80Arg) AND Hyperinsulinemic hypoglycemia, familial, 1

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Aug 16, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000192892.9

Allele description [Variation Report for NM_000352.6(ABCC8):c.239T>G (p.Met80Arg)]

NM_000352.6(ABCC8):c.239T>G (p.Met80Arg)

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.239T>G (p.Met80Arg)

Other names:

NM_000352.6(ABCC8):c.239T>G; p.Met80Arg

HGVS:

NC_000011.10:g.17474937A>C
NG_008867.1:g.6966T>G
NM_000352.6:c.239T>GMANE SELECT
NM_001287174.3:c.239T>G
NM_001351295.2:c.239T>G
NM_001351296.2:c.239T>G
NM_001351297.2:c.239T>G
NP_000343.2:p.Met80Arg
NP_001274103.1:p.Met80Arg
NP_001338224.1:p.Met80Arg
NP_001338225.1:p.Met80Arg
NP_001338226.1:p.Met80Arg
LRG_790t1:c.239T>G
LRG_790t2:c.239T>G
LRG_790:g.6966T>G
LRG_790p1:p.Met80Arg
LRG_790p2:p.Met80Arg
NC_000011.9:g.17496484A>C
NM_000352.3:c.239T>G
NR_147094.2:n.308T>G

Protein change:

M80R

Links:

dbSNP: rs797045208

NCBI 1000 Genomes Browser:

rs797045208

Molecular consequence:

NM_000352.6:c.239T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001287174.3:c.239T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351295.2:c.239T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351296.2:c.239T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351297.2:c.239T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_147094.2:n.308T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000246293	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 11, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004026584	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 16, 2023)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 31821855, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000246293

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 11, 2014)

germline

clinical testing

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

SCV004026584

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 16, 2023)

germline

curation

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

Help

Summary from all submissions

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

Citations

PubMed

Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures.

Martin GM, Sung MW, Shyng SL.

Mol Cell Endocrinol. 2020 Feb 15;502:110667. doi: 10.1016/j.mce.2019.110667. Epub 2019 Dec 9. Review.

PubMed [citation]

PMID:: 31821855
PMCID:: PMC6994177

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000246293.1

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

#	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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV004026584.1

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

Description

The p.Met80Arg variant in ABCC8 has been previously reported in 2 individuals with hyperinsulinemic hypoglycemia (PMID: 17378627, 28442472), and has been seen in 0.0009% (1/113722) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs797045208). 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: 210073) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago). Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Met80Arg variant is pathogenic (PMID: 17378627). In vitro functional studies provide some evidence that the p.Met80Arg variant may slightly impact protein function (PMID: 31821855). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Met80Arg variant is uncertain. ACMG/AMP Criteria applied: PM3, PS3_supporting, PM2_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

Last Updated: Mar 16, 2025

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