NM_003597.5(KLF11):c.1039G>T (p.Ala347Ser) AND Maturity-onset diabetes of the young type 7

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 22, 2022
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:: RCV000006871.4

Allele description [Variation Report for NM_003597.5(KLF11):c.1039G>T (p.Ala347Ser)]

NM_003597.5(KLF11):c.1039G>T (p.Ala347Ser)

Gene:

KLF11:KLF transcription factor 11 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p25.1

Genomic location:

Preferred name:

NM_003597.5(KLF11):c.1039G>T (p.Ala347Ser)

Other names:

A349S

HGVS:

NC_000002.12:g.10048376G>T
NG_017199.1:g.9822G>T
NM_001177716.2:c.988G>T
NM_001177718.2:c.988G>T
NM_003597.5:c.1039G>TMANE SELECT
NP_001171187.1:p.Ala330Ser
NP_001171189.1:p.Ala330Ser
NP_003588.1:p.Ala347Ser
NC_000002.11:g.10188503G>T
O14901:p.Ala347Ser

Protein change:

A330S; ALA349SER

Links:

UniProtKB: O14901#VAR_031524; OMIM: 603301.0001; dbSNP: rs121912645

NCBI 1000 Genomes Browser:

rs121912645

Molecular consequence:

NM_001177716.2:c.988G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001177718.2:c.988G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003597.5:c.1039G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Maturity-onset diabetes of the young type 7 (MODY7)
Synonyms:: MODY type 7; Diabetes mellitus MODY type 7; MODY KLF11 related
Identifiers:: MONDO: MONDO:0012513; MedGen: C1864839; Orphanet: 552; OMIM: 610508

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000027067	OMIM	no assertion criteria provided	Pathogenic (Mar 29, 2005)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002521418	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 22, 2022)	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

SCV000027067

OMIM

no assertion criteria provided

Pathogenic
(Mar 29, 2005)

germline

literature only

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

SCV002521418

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 22, 2022)

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	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function.

Neve B, Fernandez-Zapico ME, Ashkenazi-Katalan V, Dina C, Hamid YH, Joly E, Vaillant E, Benmezroua Y, Durand E, Bakaher N, Delannoy V, Vaxillaire M, Cook T, Dallinga-Thie GM, Jansen H, Charles MA, Clément K, Galan P, Hercberg S, Helbecque N, Charpentier G, Prentki M, et al.

Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4807-12. Epub 2005 Mar 17.

PubMed [citation]

PMID:: 15774581
PMCID:: PMC554843

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 OMIM, SCV000027067.1

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

Description

In affected members of a 4-generation family with MODY-like diabetes (MODY7; 610508), Neve et al. (2005) identified heterozygosity for a 1039G-T transversion in exon 3 of the KLF11 gene, resulting in an ala349-to-ser (A349S) substitution in the third repressor domain. The variant segregated with diabetes and glucose intolerance in all 3 generations examined and was not found in 313 patients with late-onset type II diabetes or in 313 normoglycemic individuals. Bioinformatics analysis predicted that the variant would alter the secondary protein structure of the repressor domain.

#	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

From 3billion, SCV002521418.2

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

Description

The variant is observed at an allele frequency greater than expected (0.01%) for the associated disorder in the gnomAD v2.1.1 dataset and therefore considered uncertain significant. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15774581). In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.18; 3Cnet: 0.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with KLF11 related disorder (ClinVar ID: VCV000006498 / PMID: 15774581). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Sep 29, 2024

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