NM_000352.6(ABCC8):c.4178G>A (p.Arg1393His) AND Hyperinsulinemic hypoglycemia, familial, 1

Germline classification:: Uncertain significance (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:: RCV000671471.6

Allele description [Variation Report for NM_000352.6(ABCC8):c.4178G>A (p.Arg1393His)]

NM_000352.6(ABCC8):c.4178G>A (p.Arg1393His)

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.4178G>A (p.Arg1393His)

Other names:

NM_000352.6(ABCC8):c.4178G>A; p.Arg1393His

HGVS:

NC_000011.10:g.17395872C>T
NG_008867.1:g.86031G>A
NM_000352.6:c.4178G>AMANE SELECT
NM_001287174.3:c.4181G>A
NM_001351295.2:c.4244G>A
NM_001351296.2:c.4178G>A
NM_001351297.2:c.4175G>A
NP_000343.2:p.Arg1393His
NP_001274103.1:p.Arg1394His
NP_001338224.1:p.Arg1415His
NP_001338225.1:p.Arg1393His
NP_001338226.1:p.Arg1392His
LRG_790t1:c.4178G>A
LRG_790t2:c.4181G>A
LRG_790:g.86031G>A
LRG_790p1:p.Arg1393His
LRG_790p2:p.Arg1394His
NC_000011.9:g.17417419C>T
NM_000352.3:c.4178G>A
NM_000352.4:c.4178G>A
NM_000352.5:c.4178G>A
NR_147094.2:n.4473G>A
p.ARG1393HIS

Protein change:

R1392H

Links:

dbSNP: rs769279368

NCBI 1000 Genomes Browser:

rs769279368

Molecular consequence:

NM_000352.6:c.4178G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287174.3:c.4181G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351295.2:c.4244G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351296.2:c.4178G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351297.2:c.4175G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_147094.2:n.4473G>A - 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
SCV002060360	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Uncertain significance (Nov 10, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9648840, 11457841, 9618169 Citation Link,
SCV004026509	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] 11457841, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002060360

Myriad Genetics, Inc.

criteria provided, single submitter

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

Uncertain significance
(Nov 10, 2021)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004026509

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	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy.

Shyng SL, Ferrigni T, Shepard JB, Nestorowicz A, Glaser B, Permutt MA, Nichols CG.

Diabetes. 1998 Jul;47(7):1145-51.

PubMed [citation]

PMID:: 9648840

Genetic heterogeneity in familial hyperinsulinism.

Nestorowicz A, Glaser B, Wilson BA, Shyng SL, Nichols CG, Stanley CA, Thornton PS, Permutt MA.

Hum Mol Genet. 1998 Jul;7(7):1119-28. Erratum in: Hum Mol Genet 1998 Sep;7(9):1527.

PubMed [citation]

PMID:: 9618169

See all PubMed Citations (4)

Details of each submission

From Myriad Genetics, Inc., SCV002060360.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

NM_000352.3(ABCC8):c.4178G>A(R1393H) is a missense variant classified as a variant of uncertain significance in the context of familial hyperinsulinism, ABCC8-related. R1393H has been observed in cases with relevant disease (PMID: 9618169). Functional assessments of this variant are available in the literature (PMID: 9648840, 11457841). R1393H has been observed in population frequency databases (gnomAD: SAS 0.01%). In summary, there is insufficient evidence to classify NM_000352.3(ABCC8):c.4178G>A(R1393H) as pathogenic or benign. 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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV004026509.1

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

Description

The p.Arg1393His variant in ABCC8 has been reported in 2 individuals with hyperinsulinemic hypoglycemia (PMID: 9648840, 9618169, 32041611) and has been identified in 0.008% (2/25832) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs769279368). 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: 446776) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago), Natera Inc., and Athena Diagnostics Inc., and as a variant of uncertain significance by Myriad Women's Health Inc. and Counsyl. 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.Arg1393His variant is pathogenic (Variation ID: 9088; PMID: 9648840). In vitro functional studies provide some evidence that the p.Arg1393His variant may impact protein function (PMID: 9648840, 11457841). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PP3, PM2_supporting, 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

Last Updated: Sep 29, 2024

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