NM_000352.6(ABCC8):c.4135C>T (p.Arg1379Cys) AND Monogenic diabetes

Clinical significance:Likely pathogenic (Last evaluated: Jan 22, 2020)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001249022.1

Allele description [Variation Report for NM_000352.6(ABCC8):c.4135C>T (p.Arg1379Cys)]

NM_000352.6(ABCC8):c.4135C>T (p.Arg1379Cys)

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.4135C>T (p.Arg1379Cys)
HGVS:
  • NC_000011.10:g.17395915G>A
  • NG_008867.1:g.85988C>T
  • NM_000352.4(ABCC8):c.4135C>T
  • NM_000352.6:c.4135C>TMANE SELECT
  • NM_001287174.3:c.4138C>T
  • NM_001351295.2:c.4201C>T
  • NM_001351296.2:c.4135C>T
  • NM_001351297.2:c.4132C>T
  • NP_000343.2:p.Arg1379Cys
  • NP_001274103.1:p.Arg1380Cys
  • NP_001338224.1:p.Arg1401Cys
  • NP_001338225.1:p.Arg1379Cys
  • NP_001338226.1:p.Arg1378Cys
  • LRG_790t1:c.4135C>T
  • LRG_790t2:c.4138C>T
  • LRG_790:g.85988C>T
  • LRG_790p1:p.Arg1379Cys
  • LRG_790p2:p.Arg1380Cys
  • NC_000011.9:g.17417462G>A
  • NM_000352.4(ABCC8):c.4135C>T
  • NM_000352.4:c.4135C>T
  • NR_147094.2:n.4430C>T
  • p.Arg1379Cys
Protein change:
R1378C; ARG1379CYS
Links:
OMIM: 600509.0019; dbSNP: rs137852673
NCBI 1000 Genomes Browser:
rs137852673
Molecular consequence:
  • NM_000352.6:c.4135C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287174.3:c.4138C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351295.2:c.4201C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351296.2:c.4135C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351297.2:c.4132C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_147094.2:n.4430C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001422929Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedLikely pathogenic
(Jan 22, 2020)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood.

Flanagan SE, Patch AM, Mackay DJ, Edghill EL, Gloyn AL, Robinson D, Shield JP, Temple K, Ellard S, Hattersley AT.

Diabetes. 2007 Jul;56(7):1930-7. Epub 2007 Apr 19. Erratum in: Diabetes. 2008 Feb;57(2):523.

PubMed [citation]
PMID:
17446535
PMCID:
PMC7611811

Increased ATPase activity produced by mutations at arginine-1380 in nucleotide-binding domain 2 of ABCC8 causes neonatal diabetes.

de Wet H, Rees MG, Shimomura K, Aittoniemi J, Patch AM, Flanagan SE, Ellard S, Hattersley AT, Sansom MS, Ashcroft FM.

Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):18988-92. Epub 2007 Nov 19.

PubMed [citation]
PMID:
18025464
PMCID:
PMC2141895
See all PubMed Citations (4)

Details of each submission

From Broad Institute Rare Disease Group, Broad Institute, SCV001422929.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (4)

Description

The p.Arg1379Cys (sometimes called p.Arg1380Cys) variant in ABCC8 has been reported in 7 individuals with Monogenic Diabetes, segregated with disease in 4 affected relatives from 1 family (PMID: 16885549, 17446535, 25306193), and has been identified in 0.003286% (1/30434) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852673). 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. Trio analysis showed this variant to be de novo with unconfirmed maternity and paternity in one individual reported in the literature (PMID: 17446535). This variant has also been reported pathogenic in ClinVar (Variation ID: 9105). In vitro functional studies provide some evidence that the p.Arg1379Cys variant may slightly increase the rate of ATP hydrolysis (PMID: 18025464). 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. Three additional variants with a different amino acid change at the same position, (p.Arg1379His, p.Arg1379Leu and p.Arg1379Ser), have been reported in association with disease in ClinVar or have been curated likely pathogenic or as variants of uncertain significance by our study, supporting that a change at this position may not be tolerated (Variation ID: 35615, 35614). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM6, PM5_supporting, PS3_supporting, PM2_Supporting, PP3, PS4_Supporting, PP1 (Richards 2015).

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

Last Updated: Nov 27, 2021

Support Center