NM_000352.6(ABCC8):c.4411G>A (p.Asp1471Asn) 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:: RCV000169299.9

Allele description [Variation Report for NM_000352.6(ABCC8):c.4411G>A (p.Asp1471Asn)]

NM_000352.6(ABCC8):c.4411G>A (p.Asp1471Asn)

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.4411G>A (p.Asp1471Asn)

Other names:

NM_000352.6(ABCC8):c.4411G>A; p.Asp1471Asn

HGVS:

NC_000011.10:g.17395172C>T
NG_008867.1:g.86731G>A
NM_000352.6:c.4411G>AMANE SELECT
NM_001287174.3:c.4414G>A
NM_001351295.2:c.4477G>A
NM_001351296.2:c.4411G>A
NM_001351297.2:c.4408G>A
NP_000343.2:p.Asp1471Asn
NP_001274103.1:p.Asp1472Asn
NP_001338224.1:p.Asp1493Asn
NP_001338225.1:p.Asp1471Asn
NP_001338226.1:p.Asp1470Asn
LRG_790t1:c.4411G>A
LRG_790t2:c.4414G>A
LRG_790:g.86731G>A
LRG_790p1:p.Asp1471Asn
LRG_790p2:p.Asp1472Asn
NC_000011.9:g.17416719C>T
NM_000352.3:c.4411G>A
NM_000352.4:c.4411G>A
NM_000352.5:c.4411G>A
NR_147094.2:n.4706G>A

Protein change:

D1470N

Links:

dbSNP: rs72559716

NCBI 1000 Genomes Browser:

rs72559716

Molecular consequence:

NM_000352.6:c.4411G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287174.3:c.4414G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351295.2:c.4477G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351296.2:c.4411G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351297.2:c.4408G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_147094.2:n.4706G>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

Recent activity

Clear Turn Off Turn On

Tssr794 AND (alive[prop]) (0)
Gene

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220618	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Aug 21, 2014)	unknown	literature only	PubMed (8) [See all records that cite these PMIDs] 17378627, 14764815, 20685672, 18988933, 15562009, 10720932, 20799350, 17466004 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000914500	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Nov 1, 2018)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 18988933, 23345197, 24616771, 20685672, 17466004, 30352420, 15562009, 14764815, 17378627 Citation Link,
SCV004026579	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 (2) [See all records that cite these PMIDs] 17466004, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000220618

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Aug 21, 2014)

unknown

literature only

PubMed (8)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000914500

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(Nov 1, 2018)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV004026579

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 (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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Familial hyperinsulinism and pancreatic beta-cell ATP-sensitive potassium channels.

Sharma N, Crane A, Gonzalez G, Bryan J, Aguilar-Bryan L.

Kidney Int. 2000 Mar;57(3):803-8. Review.

PubMed [citation]

PMID:: 10720932

Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains.

Kelly L, Fukushima H, Karchin R, Gow JM, Chinn LW, Pieper U, Segal MR, Kroetz DL, Sali A.

Protein Sci. 2010 Nov;19(11):2110-21. doi: 10.1002/pro.491.

PubMed [citation]

PMID:: 20799350
PMCID:: PMC3005782

See all PubMed Citations (12)

Details of each submission

From Counsyl, SCV000220618.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (8)

#	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 Illumina Laboratory Services, Illumina, SCV000914500.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Across a selection of the available literature, the ABCC8 c.4411G>A (p.Asp1471Asn) missense variant, also referred to as c.4414G>A (p. Asp1472Asn), has been identified in12 individuals with hyperinsulinism, six in a compound heterozygous state and six in a heterozygous state (Giurgea et al. 2004; Henwood et al. 2005; Greer et al. 2007; Muzyamba et al. 2007; Brunetti-Pierri et al. 2008; BellannÃ©-Chantelot et al. 2009; Chandran et al. 2013; Kapoor et al. 2013; Xu et al. 2018). Muzyamba et al. (2007) reported a child with hyperinsulinism and focal disease who is heterozygous for two variants inherited from his father (p.Gly228Asp and p.Asp1471Asn) and one from his mother. The p.Gly228Asp and p.Asp1471Asn variants led to intracellular retention of the channel complex and loss of function, though it is unclear if one of these variants contributed to the loss of function alone. The p.Asp1471Asn variant was absent from 548 controls and is reported at a frequency of 0.00002 in the total population of the Genome Aggregation Database. Based on the collective evidence, the p.Asp1471Asn variant is classified as pathogenic for ABCC8-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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, SCV004026579.1

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

Description

The p.Asp1471Asn variant in ABCC8 has been reported in at least 6 individuals with hyperinsulinemic hypoglycemia (PMID: 20685672, 30186238, 18988933, 24616771, 14764815, 17378627), and has been identified in 0.007% (1/13984) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs72559716). 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#: 188931) and has been interpreted as pathogenic or likely pathogenic by multiple sources. Of the 6 affected individuals, 4 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Asp1471Asn variant is pathogenic (Variation ID: 996301; PMID: 30186238, 18988933, 14764815, 17378627). In vitro functional studies provide some evidence that the p.Asp1471Asn variant may slightly impact protein function (PMID: 17466004). 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. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Asp1471His, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 1452717). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very-strong, PM5, PP3, PS3_supporting, PP2_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 16, 2024

ClinVar

Relating variation to medicine