NM_000352.6(ABCC8):c.4369G>A (p.Ala1457Thr) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 22, 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:: RCV001820080.5

Allele description [Variation Report for NM_000352.6(ABCC8):c.4369G>A (p.Ala1457Thr)]

NM_000352.6(ABCC8):c.4369G>A (p.Ala1457Thr)

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.4369G>A (p.Ala1457Thr)

HGVS:

NC_000011.10:g.17395214C>T
NG_008867.1:g.86689G>A
NM_000352.6:c.4369G>AMANE SELECT
NM_001287174.3:c.4372G>A
NM_001351295.2:c.4435G>A
NM_001351296.2:c.4369G>A
NM_001351297.2:c.4366G>A
NP_000343.2:p.Ala1457Thr
NP_001274103.1:p.Ala1458Thr
NP_001338224.1:p.Ala1479Thr
NP_001338225.1:p.Ala1457Thr
NP_001338226.1:p.Ala1456Thr
LRG_790t1:c.4369G>A
LRG_790t2:c.4372G>A
LRG_790:g.86689G>A
LRG_790p1:p.Ala1457Thr
LRG_790p2:p.Ala1458Thr
NC_000011.9:g.17416761C>T
NM_000352.4:c.4369G>A
NR_147094.2:n.4664G>A

Protein change:

A1456T

Links:

dbSNP: rs72559717

NCBI 1000 Genomes Browser:

rs72559717

Molecular consequence:

NM_000352.6:c.4369G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287174.3:c.4372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351295.2:c.4435G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351296.2:c.4369G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351297.2:c.4366G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_147094.2:n.4664G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002069036	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 4, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004295371	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 27538677, 12627323, 21536946, 31464105, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002069036

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 4, 2021)

germline

clinical testing

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

SCV004295371

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2023)

germline

clinical testing

PubMed (5)
[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	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

Ovsyannikova AK, Rymar OD, Shakhtshneider EV, Klimontov VV, Koroleva EA, Myakina NE, Voevoda MI.

Diabetes Ther. 2016 Sep;7(3):591-600. doi: 10.1007/s13300-016-0192-9. Epub 2016 Aug 18.

PubMed [citation]

PMID:: 27538677
PMCID:: PMC5014798

See all PubMed Citations (6)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002069036.1

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

Description

DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.4369G>A, in exon 36 that results in an amino acid change, p.Ala1457Thr. This sequence changed has not been described in the population databases such as ExAC and gnomAD (dbSNP rs72559717). The p.Ala1457Thr change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is known to be functional. The p.Ala1457Thr sequence change has previously been described in the heterozygous state in a patient with ABCC8-related hyperinsulinism, inherited from the patient's unaffected father (PMID: 21536946). This sequence change has also been reported in the compound heterozygous state with a second ABCC8 sequence change in a patient with severe diazoxide unresponsive hyperinsulinism (PMID: 12627323). Functional studies provided evidence to suggest that this variant impairs normal function of the ABCC8 (SUR1) protein (PMID: 21536946). This sequence change has been reported in multiple patients who showed responsiveness to diazoxide and inherited the variant in an autosomal dominant manner (PMID: 31464105). Thus, the p.Ala1457Thr pathogenic sequence change may function in an autosomal dominant manner with reduced penetrance, and may also be associated with autosomal recessive disease.

#	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 Invitae, SCV004295371.1

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1457 of the ABCC8 protein (p.Ala1457Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital hyperinsulinism and/or autosomal dominant early onset diabetes (PMID: 21536946, 27538677, 31464105). In at least one individual the variant was observed to be de novo. This variant is also known as A1458T. ClinVar contains an entry for this variant (Variation ID: 1065615). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 12627323, 21536946, 31464105). For these reasons, this variant has been 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

Last Updated: Feb 20, 2024

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