NM_000207.3(INS):c.115C>T (p.Leu39Phe) AND Maturity-onset diabetes of the young type 10

Germline classification:: Likely pathogenic (1 submission)
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:: RCV002466269.1

Allele description [Variation Report for NM_000207.3(INS):c.115C>T (p.Leu39Phe)]

NM_000207.3(INS):c.115C>T (p.Leu39Phe)

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.115C>T (p.Leu39Phe)

HGVS:

NC_000011.10:g.2160857G>A
NG_007114.1:g.5338C>T
NG_050578.1:g.5353C>T
NM_000207.3:c.115C>TMANE SELECT
NM_001042376.3:c.115C>T
NM_001185097.2:c.115C>T
NM_001185098.2:c.115C>T
NM_001291897.2:c.115C>T
NP_000198.1:p.Leu39Phe
NP_001035835.1:p.Leu39Phe
NP_001172026.1:p.Leu39Phe
NP_001172027.1:p.Leu39Phe
NP_001278826.1:p.Leu39Phe
GRCH37chr11:g.2182087G>A
NC_000011.9:g.2182087G>A
NM_000207.2:c.115C>T
NR_003512.4:n.174C>T

Protein change:

L39F

Links:

dbSNP: rs2133676660

NCBI 1000 Genomes Browser:

rs2133676660

Molecular consequence:

NM_000207.3:c.115C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042376.3:c.115C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001185097.2:c.115C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001185098.2:c.115C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001291897.2:c.115C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_003512.4:n.174C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Maturity-onset diabetes of the young type 10
Identifiers:: MONDO: MONDO:0013240; MedGen: C3150617; Orphanet: 552; OMIM: 613370

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002758648	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	inherited	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24411943, 25781672, 20007936, 27634015, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002758648

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

inherited

clinical testing

PubMed (5)
[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	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man.

Flanagan SE, De Franco E, Lango Allen H, Zerah M, Abdul-Rasoul MM, Edge JA, Stewart H, Alamiri E, Hussain K, Wallis S, de Vries L, Rubio-Cabezas O, Houghton JA, Edghill EL, Patch AM, Ellard S, Hattersley AT.

Cell Metab. 2014 Jan 7;19(1):146-54. doi: 10.1016/j.cmet.2013.11.021.

PubMed [citation]

PMID:: 24411943
PMCID:: PMC3887257

Sulfonylurea in the treatment of neonatal diabetes mellitus children with heterogeneous genetic backgrounds.

Zhang M, Chen X, Shen S, Li T, Chen L, Hu M, Cao L, Cheng R, Zhao Z, Luo F.

J Pediatr Endocrinol Metab. 2015 Jul;28(7-8):877-84. doi: 10.1515/jpem-2014-0429.

PubMed [citation]

PMID:: 25781672

See all PubMed Citations (5)

Details of each submission

From Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital, SCV002758648.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	PubMed (5)

Description

A heterozygous likely pathogenic missense variant was identified in exon 2 of the INS gene (NM_000207.2:c.115C>T, p.Leu39Phe). Pathogenic variants in INS are a rare (<1%) cause of autosomal dominant Maturity-Onset Diabetes of the Young (MODY type 10) (https://www.ncbi.nlm.nih.gov/books/NBK500456). The INS p.Leu39Phe variant substitutes the leucine at position 39 with phenylalanine and has not been observed in large population studies (Genome Aggregation Database). This residue is within the insulin B chain (amino acids 25-54, UniProtKB # P01308), a critical functional domain. The majority of in silico tools predict this missense variant has a damaging effect. While the p.Leu39Phe variant has not been reported before, other missense changes at this position (p.Leu39Pro and p.Leu39Val) have been reported in individuals with neonatal diabetes (PMID: 24411943, PMID: 25781672). Different missense changes within this domain have been reported (p.Leu30Met, p.Leu30Arg, p.Val42Ala) in individuals with a MODY phenotype (PMID: 27659712, PMID: 20007936, PMID: 27634015).

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

Last Updated: Jan 13, 2025

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