NM_000352.6(ABCC8):c.3641G>A (p.Arg1214Gln) AND Hyperinsulinemic hypoglycemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (3 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:: RCV001290313.8

Allele description [Variation Report for NM_000352.6(ABCC8):c.3641G>A (p.Arg1214Gln)]

NM_000352.6(ABCC8):c.3641G>A (p.Arg1214Gln)

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.3641G>A (p.Arg1214Gln)

Other names:

p.Arg1214Gln; NM_000352.6(ABCC8):c.3641G>A

HGVS:

NC_000011.10:g.17402670C>T
NG_008867.1:g.79233G>A
NM_000352.6:c.3641G>AMANE SELECT
NM_001287174.3:c.3644G>A
NM_001351295.2:c.3707G>A
NM_001351296.2:c.3641G>A
NM_001351297.2:c.3638G>A
NP_000343.2:p.Arg1214Gln
NP_001274103.1:p.Arg1215Gln
NP_001338224.1:p.Arg1236Gln
NP_001338225.1:p.Arg1214Gln
NP_001338226.1:p.Arg1213Gln
LRG_790t1:c.3641G>A
LRG_790t2:c.3644G>A
LRG_790:g.79233G>A
LRG_790p1:p.Arg1214Gln
LRG_790p2:p.Arg1215Gln
NC_000011.9:g.17424217C>T
NM_000352.3:c.3641G>A
NM_000352.5:c.3641G>A
NR_147094.2:n.3790G>A

Protein change:

R1213Q

Links:

dbSNP: rs367850779

NCBI 1000 Genomes Browser:

rs367850779

Molecular consequence:

NM_000352.6:c.3641G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287174.3:c.3644G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351295.2:c.3707G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351296.2:c.3641G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351297.2:c.3638G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_147094.2:n.3790G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV001478360	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 9, 2020)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002600280	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004026522	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 16, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001478360

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 9, 2020)

inherited

clinical testing

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

SCV002600280

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 1, 2022)

germline

clinical testing

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

SCV004026522

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 16, 2023)

germline

curation

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

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	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	inherited	yes	3	1	not provided	3	yes	clinical testing

Citations

PubMed

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 Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV001478360.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	3	not provided	discovery		3	not provided	1	not provided

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV002600280.1

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

Description

A compound heterozygous variation in exon 29 of the ABCCB gene that results in the amino acid substitution of Glutamine for Arginine at codon 1214 was detected. The observed variant c.3641G>A (p.Arg1214Gln) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

#	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		1	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV004026522.1

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

Description

The p.Arg1214Gln variant in ABCC8 has been reported in at least 5 individuals with hyperinsulinemic hypoglycemia (PMID: 20685672, 15562009, 9618169, 9648840, 14715863, 14692646), and has been identified in 0.005% (1/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs367850779). 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: 632619) and has been interpreted as pathogenic by Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Kasturba Medical College (Manipal, Manipal Academy of Higher Education), Invitae, Foundation for Research in Genetics and Endocrinology (FRIGE's Institute of Human Genetics), Natera Inc., and Fulgent Genetics. Of the 5 affected individuals, 2 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg1214Gln variant is pathogenic (Variation ID: 9088, 371380; PMID: 9648840, 14692646). In vitro functional studies provide some evidence that the p.Arg1214Gln variant may slightly impact protein function (PMID: 9648840). 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_strong, 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: Dec 14, 2024

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