NM_000207.3(INS):c.137G>A (p.Arg46Gln) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 28, 2023
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:: RCV001851851.3

Allele description [Variation Report for NM_000207.3(INS):c.137G>A (p.Arg46Gln)]

NM_000207.3(INS):c.137G>A (p.Arg46Gln)

Genes:

INS-IGF2:INS-IGF2 readthrough [Gene - HGNC]
INS:insulin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_000207.3(INS):c.137G>A (p.Arg46Gln)

HGVS:

NC_000011.10:g.2160835C>T
NG_007114.1:g.5360G>A
NG_050578.1:g.5375G>A
NM_000207.3:c.137G>AMANE SELECT
NM_001042376.3:c.137G>A
NM_001185097.2:c.137G>A
NM_001185098.2:c.137G>A
NM_001291897.2:c.137G>A
NP_000198.1:p.Arg46Gln
NP_001035835.1:p.Arg46Gln
NP_001172026.1:p.Arg46Gln
NP_001172027.1:p.Arg46Gln
NP_001278826.1:p.Arg46Gln
NC_000011.9:g.2182065C>T
NM_000207.2:c.137G>A
NR_003512.4:n.196G>A
P01308:p.Arg46Gln

Protein change:

R46Q; ARG46GLN

Links:

UniProtKB: P01308#VAR_063729; UniProtKB/Swiss-Prot: VAR_063729; OMIM: 176730.0015; dbSNP: rs121908260

NCBI 1000 Genomes Browser:

rs121908260

Molecular consequence:

NM_000207.3:c.137G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042376.3:c.137G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001185097.2:c.137G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001185098.2:c.137G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001291897.2:c.137G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_003512.4:n.196G>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
SCV002297001	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 28, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18192540, 20226046, 28478482, 20948967, 25423173, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002297001

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 28, 2023)

germline

clinical testing

PubMed (6)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes.

Molven A, Ringdal M, Nordbø AM, Raeder H, Støy J, Lipkind GM, Steiner DF, Philipson LH, Bergmann I, Aarskog D, Undlien DE, Joner G, Søvik O; Norwegian Childhood Diabetes Study Group., Bell GI, Njølstad PR.

Diabetes. 2008 Apr;57(4):1131-5. doi: 10.2337/db07-1467. Epub 2008 Jan 11.

PubMed [citation]

PMID:: 18192540

Further evidence that mutations in INS can be a rare cause of Maturity-Onset Diabetes of the Young (MODY).

Boesgaard TW, Pruhova S, Andersson EA, Cinek O, Obermannova B, Lauenborg J, Damm P, Bergholdt R, Pociot F, Pisinger C, Barbetti F, Lebl J, Pedersen O, Hansen T.

BMC Med Genet. 2010 Mar 12;11:42. doi: 10.1186/1471-2350-11-42.

PubMed [citation]

PMID:: 20226046
PMCID:: PMC2848224

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV002297001.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 46 of the INS protein (p.Arg46Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young type (PMID: 18192540, 20226046, 28478482). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13391). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects INS function (PMID: 20948967, 25423173). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Last Updated: Feb 20, 2024

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