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NM_000352.6(ABCC8):c.886G>A (p.Gly296Arg) AND Monogenic diabetes

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 22, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001249020.10

Allele description [Variation Report for NM_000352.6(ABCC8):c.886G>A (p.Gly296Arg)]

NM_000352.6(ABCC8):c.886G>A (p.Gly296Arg)

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.886G>A (p.Gly296Arg)
HGVS:
  • NC_000011.10:g.17460613C>T
  • NG_008867.1:g.21290G>A
  • NM_000352.4(ABCC8):c.886G>A
  • NM_000352.6:c.886G>AMANE SELECT
  • NM_001287174.3:c.886G>A
  • NM_001351295.2:c.886G>A
  • NM_001351296.2:c.883G>A
  • NM_001351297.2:c.883G>A
  • NP_000343.2:p.Gly296Arg
  • NP_001274103.1:p.Gly296Arg
  • NP_001338224.1:p.Gly296Arg
  • NP_001338225.1:p.Gly295Arg
  • NP_001338226.1:p.Gly295Arg
  • LRG_790t1:c.886G>A
  • LRG_790t2:c.886G>A
  • LRG_790:g.21290G>A
  • LRG_790p1:p.Gly296Arg
  • LRG_790p2:p.Gly296Arg
  • NC_000011.9:g.17482160C>T
  • NM_000352.3:c.886G>A
  • NM_000352.4(ABCC8):c.886G>A
  • NM_000352.4:c.886G>A
  • NM_000352.5:c.886G>A
  • NM_000352.6:c.886G>A
  • NR_147094.2:n.952G>A
Protein change:
G295R
Links:
dbSNP: rs148529020
NCBI 1000 Genomes Browser:
rs148529020
Molecular consequence:
  • NM_000352.6:c.886G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287174.3:c.886G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351295.2:c.886G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351296.2:c.883G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351297.2:c.883G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_147094.2:n.952G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Monogenic diabetes
Identifiers:
MONDO: MONDO:0015967; MedGen: C3888631

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001422927Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jan 22, 2020) 		germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Compound heterozygous mutations in the SUR1 (ABCC 8) subunit of pancreatic K(ATP) channels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits.

Lin YW, Akrouh A, Hsu Y, Hughes N, Nichols CG, De León DD.

Channels (Austin). 2012 Mar-Apr;6(2):133-8. doi: 10.4161/chan.19980. Epub 2012 Mar 1.

PubMed [citation]
PMID:
22562119
PMCID:
PMC3396690

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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422927.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The p.Gly296Arg variant in ABCC8 has been reported in 1 Chinese and 1 Pakistan individuals, in the heterozygous or compound heterozygous state, with Monogenic Diabetes (PMID: 22562119, 26839896), and has been identified in 0.004013% (1/24920) of African chromosomes, 0.003267% (1/30610) of South Asian chromosomes, and 0.001555% (2/128636) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148529020). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 35624). In vitro functional studies provide some evidence that the p.Gly296Arg variant may slightly increase protein activity (PMID: 22562119). 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. This variant is located in the L0 domain, which has been associated with changes in the K-ATP channel of the protein and diabetes (PMID: 22562119). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS3_Supporting, PM1_Supporting (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 29, 2024