NM_000352.6(ABCC8):c.4612C>T (p.Arg1538Ter) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 19, 2024
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:: RCV001379884.9

Allele description [Variation Report for NM_000352.6(ABCC8):c.4612C>T (p.Arg1538Ter)]

NM_000352.6(ABCC8):c.4612C>T (p.Arg1538Ter)

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.4612C>T (p.Arg1538Ter)

HGVS:

NC_000011.10:g.17393125G>A
NG_008867.1:g.88778C>T
NG_012446.1:g.535C>T
NM_000352.6:c.4612C>TMANE SELECT
NM_001287174.3:c.4615C>T
NM_001351295.2:c.4678C>T
NM_001351296.2:c.4612C>T
NM_001351297.2:c.4609C>T
NP_000343.2:p.Arg1538Ter
NP_001274103.1:p.Arg1539Ter
NP_001338224.1:p.Arg1560Ter
NP_001338225.1:p.Arg1538Ter
NP_001338226.1:p.Arg1537Ter
LRG_790t1:c.4612C>T
LRG_790t2:c.4615C>T
LRG_790:g.88778C>T
LRG_790p1:p.Arg1538Ter
LRG_790p2:p.Arg1539Ter
NC_000011.9:g.17414672G>A
NM_000352.3:c.4612C>T
NR_147094.2:n.4907C>T

Protein change:

R1537*

Links:

dbSNP: rs1411638309

NCBI 1000 Genomes Browser:

rs1411638309

Molecular consequence:

NR_147094.2:n.4907C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000352.6:c.4612C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001287174.3:c.4615C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351295.2:c.4678C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351296.2:c.4612C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351297.2:c.4609C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001577769	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11867634, 15562009, 23275527, 28492532
SCV003924894	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Nov 11, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001577769

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 19, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV003924894

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Nov 11, 2022)

germline

clinical testing

Citation Link

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

Identification of a familial hyperinsulinism-causing mutation in the sulfonylurea receptor 1 that prevents normal trafficking and function of KATP channels.

Taschenberger G, Mougey A, Shen S, Lester LB, LaFranchi S, Shyng SL.

J Biol Chem. 2002 May 10;277(19):17139-46. Epub 2002 Feb 26.

PubMed [citation]

PMID:: 11867634

Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes.

Henwood MJ, Kelly A, Macmullen C, Bhatia P, Ganguly A, Thornton PS, Stanley CA.

J Clin Endocrinol Metab. 2005 Feb;90(2):789-94. Epub 2004 Nov 23.

PubMed [citation]

PMID:: 15562009

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001577769.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Arg1538*) in the ABCC8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the ABCC8 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ABCC8-related conditions. ClinVar contains an entry for this variant (Variation ID: 556392). This variant disrupts a region of the ABCC8 protein in which other variant(s) (p.Leu1543Pro) have been determined to be pathogenic (PMID: 11867634, 15562009, 23275527). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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

From GeneDx, SCV003924894.1

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

Description

Identified as heterozygous in a patient with hyperinsulinism in published literature (De Franco et al., 2020); Nonsense variant predicted to result in protein truncation, as the last 44 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32027066)

#	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

Last Updated: Mar 16, 2025

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