NM_173851.3(SLC30A8):c.412C>T (p.Arg138Ter) AND Type 2 diabetes mellitus

Germline classification:: protective (1 submission)
Last evaluated:: Apr 1, 2014
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV000129930.13

Allele description [Variation Report for NM_173851.3(SLC30A8):c.412C>T (p.Arg138Ter)]

NM_173851.3(SLC30A8):c.412C>T (p.Arg138Ter)

Gene:

SLC30A8:solute carrier family 30 member 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q24.11

Genomic location:

Preferred name:

NM_173851.3(SLC30A8):c.412C>T (p.Arg138Ter)

HGVS:

NC_000008.11:g.117153084C>T
NG_016991.1:g.207812C>T
NM_001172811.2:c.265C>T
NM_001172813.2:c.265C>T
NM_001172814.2:c.265C>T
NM_001172815.3:c.265C>T
NM_173851.3:c.412C>TMANE SELECT
NP_001166282.1:p.Arg89Ter
NP_001166284.1:p.Arg89Ter
NP_001166285.1:p.Arg89Ter
NP_001166286.1:p.Arg89Ter
NP_776250.2:p.Arg138Ter
NP_776250.2:p.Arg138Ter
NC_000008.10:g.118165323C>T
NM_173851.2:c.412C>T

Protein change:

R138*; ARG138TER

Links:

OMIM: 611145.0002; dbSNP: rs200185429

NCBI 1000 Genomes Browser:

rs200185429

Molecular consequence:

NM_001172811.2:c.265C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001172813.2:c.265C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001172814.2:c.265C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001172815.3:c.265C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_173851.3:c.412C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Type 2 diabetes mellitus
Synonyms:: DIABETES MELLITUS, TYPE 2, PROTECTION AGAINST; Type II diabetes mellitus; Diabetes mellitus, noninsulin-dependent, late onset
Identifiers:: MONDO: MONDO:0005148; MeSH: D003924; MedGen: C0011860; OMIM: 125853; Human Phenotype Ontology: HP:0005978

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184748	OMIM	no assertion criteria provided	protective (Apr 1, 2014)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 24584071, 31676859

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184748

OMIM

no assertion criteria provided

protective
(Apr 1, 2014)

germline

literature only

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, Mahajan A, Fuchsberger C, Atzmon G, Benediktsson R, Blangero J, Bowden DW, Brandslund I, Brosnan J, Burslem F, Chambers J, Cho YS, Christensen C, Douglas DA, Duggirala R, Dymek Z, Farjoun Y, et al.

Nat Genet. 2014 Apr;46(4):357-63. doi: 10.1038/ng.2915. Epub 2014 Mar 2.

PubMed [citation]

PMID:: 24584071
PMCID:: PMC4051628

Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.

Dwivedi OP, Lehtovirta M, Hastoy B, Chandra V, Krentz NAJ, Kleiner S, Jain D, Richard AM, Abaitua F, Beer NL, Grotz A, Prasad RB, Hansson O, Ahlqvist E, Krus U, Artner I, Suoranta A, Gomez D, Baras A, Champon B, Payne AJ, Moralli D, et al.

Nat Genet. 2019 Nov;51(11):1596-1606. doi: 10.1038/s41588-019-0513-9. Epub 2019 Nov 1.

PubMed [citation]

PMID:: 31676859
PMCID:: PMC6858874

Details of each submission

From OMIM, SCV000184748.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In combined analysis of 48,115 individuals, Flannick et al. (2014) identified a c.412C-T transition in the SLC30A8 gene, resulting in an arg138-to-ter (R138X) substitution that conferred protection against type 2 diabetes mellitus (T2D; see 125853): heterozygosity for R138X was estimated to yield a 53% reduction in T2D risk (p = 0.0067). Overexpression of the R138X variant in HeLa cells showed low to undetectable protein levels by protein blot analysis or immunofluorescence staining, despite RNA transcript levels that were similar to wildtype.

Using human induced pluripotent stem cell-derived beta-like cells heterozygous for R138X, Dwivedi et al. (2019) confirmed that R138X reduced SLC30A8 expression due to nonsense-mediated decay, leading to haploinsufficiency. Knockdown of SLC30A8 in human beta cells reduced Zn(2+) content and enhanced insulin secretion, proinsulin processing, and cell viability in response to glucose challenge. Likewise, mice carrying the human R138X allele showed enhanced insulin secretion and proinsulin processing when fed a high-fat diet. The R138X protein showed punctate distribution consistent with localization to secretory granules when overexpressed in a rat insulinoma cell line, but it had no impact on cytosolic free Zn(2+). The authors concluded that loss of SLC30A8 function protects against T2D via enhanced insulin secretion.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 26, 2024

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