NM_000352.6(ABCC8):c.4253G>A (p.Arg1418His) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 23, 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:: RCV001202457.11

Allele description

NM_000352.6(ABCC8):c.4253G>A (p.Arg1418His)

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.4253G>A (p.Arg1418His)

HGVS:

NC_000011.10:g.17395664C>T
NG_008867.1:g.86239G>A
NM_000352.6:c.4253G>AMANE SELECT
NM_001287174.3:c.4256G>A
NM_001351295.2:c.4319G>A
NM_001351296.2:c.4253G>A
NM_001351297.2:c.4250G>A
NP_000343.2:p.Arg1418His
NP_001274103.1:p.Arg1419His
NP_001338224.1:p.Arg1440His
NP_001338225.1:p.Arg1418His
NP_001338226.1:p.Arg1417His
LRG_790t1:c.4253G>A
LRG_790t2:c.4256G>A
LRG_790:g.86239G>A
LRG_790p1:p.Arg1418His
LRG_790p2:p.Arg1419His
NC_000011.9:g.17417211C>T
NM_000352.3:c.4253G>A
NM_000352.4:c.4253G>A
NR_147094.2:n.4548G>A

Protein change:

R1417H

Links:

dbSNP: rs1446306735

NCBI 1000 Genomes Browser:

rs1446306735

Molecular consequence:

NM_000352.6:c.4253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287174.3:c.4256G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351295.2:c.4319G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351296.2:c.4253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351297.2:c.4250G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_147094.2:n.4548G>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
SCV001373570	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 23, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15579781, 23275527, 25720052, 23798684, 24401662, 26316440, 28492532
SCV002601237	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Nov 12, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001373570

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 23, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002601237

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Nov 12, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.

Tornovsky S, Crane A, Cosgrove KE, Hussain K, Lavie J, Heyman M, Nesher Y, Kuchinski N, Ben-Shushan E, Shatz O, Nahari E, Potikha T, Zangen D, Tenenbaum-Rakover Y, de Vries L, Argente J, Gracia R, Landau H, Eliakim A, Lindley K, Dunne MJ, Aguilar-Bryan L, et al.

J Clin Endocrinol Metab. 2004 Dec;89(12):6224-34.

PubMed [citation]

PMID:: 15579781

Genotype and phenotype correlations in 417 children with congenital hyperinsulinism.

Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A.

J Clin Endocrinol Metab. 2013 Feb;98(2):E355-63. doi: 10.1210/jc.2012-2169. Epub 2012 Dec 28.

PubMed [citation]

PMID:: 23275527
PMCID:: PMC3565119

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001373570.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1418 of the ABCC8 protein (p.Arg1418His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive familial hyperinsulinism (PMID: 15579781, 23275527, 25720052). This variant is also known as R1419H. ClinVar contains an entry for this variant (Variation ID: 552540). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 23798684). This variant disrupts the p.Arg1419 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been observed in individuals with ABCC8-related conditions (PMID: 24401662, 26316440), which suggests that this may be a clinically significant amino acid residue. 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, SCV002601237.2

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

Description

Also known as p.R1419H; Published functional studies demonstrate a severe trafficking defect that results in a loss of potassium channel function (Tornovsky et al., 2004; Harel et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25781536, 23798684, 25720052, 34304300, 23275527, 23226049, 23345197, 15579781, 34631896)

#	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: Sep 16, 2024

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