NM_000352.6(ABCC8):c.1969C>T (p.Arg657Trp) AND Type 2 diabetes mellitus

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 4, 2021
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:: RCV002225204.4

Allele description [Variation Report for NM_000352.6(ABCC8):c.1969C>T (p.Arg657Trp)]

NM_000352.6(ABCC8):c.1969C>T (p.Arg657Trp)

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.1969C>T (p.Arg657Trp)

HGVS:

NC_000011.10:g.17428360G>A
NG_008867.1:g.53543C>T
NM_000352.6:c.1969C>TMANE SELECT
NM_001287174.3:c.1969C>T
NM_001351295.2:c.2035C>T
NM_001351296.2:c.1966C>T
NM_001351297.2:c.1966C>T
NP_000343.2:p.Arg657Trp
NP_001274103.1:p.Arg657Trp
NP_001338224.1:p.Arg679Trp
NP_001338225.1:p.Arg656Trp
NP_001338226.1:p.Arg656Trp
LRG_790t1:c.1969C>T
LRG_790t2:c.1969C>T
LRG_790:g.53543C>T
LRG_790p1:p.Arg657Trp
LRG_790p2:p.Arg657Trp
NC_000011.9:g.17449907G>A
NM_000352.5:c.1969C>T
NR_147094.2:n.2035C>T

Protein change:

R656W

Links:

dbSNP: rs778117119

NCBI 1000 Genomes Browser:

rs778117119

Molecular consequence:

NM_000352.6:c.1969C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001287174.3:c.1969C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351295.2:c.2035C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351296.2:c.1966C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351297.2:c.1966C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_147094.2:n.2035C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV002503763	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 4, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002503763

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 4, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Citations

PubMed

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 Molecular Genetics, Royal Melbourne Hospital, SCV002503763.2

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

Description

This sequence change is predicted to replace arginine with tryptophan at codon 657 of the ABCC8 protein (p.(Arg657Trp)). The arginine residue is not conserved, with tryptophan present in multiple primates (100 vertebrates, UCSC), and is not located in a known functional domain. There is a large physicochemical difference between arginine and tryptophan. The variant is present in a European (non-Finnish) population cohort at a frequency of 0.006% (rs778117119, 7/113,442 alleles, 0 homozygotes in gnomAD v2.1), and has not been reported in the relevant medical literature or databases. Multiple lines of computational evidence predict a benign effect for the missense substitution (BP4; 5/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: BP4.

#	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: Nov 18, 2024

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