NM_175914.5(HNF4A):c.340C>T (p.Arg114Trp) AND Maturity onset diabetes mellitus in young

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 15, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002453254.4

Allele description

NM_175914.5(HNF4A):c.340C>T (p.Arg114Trp)

Gene:

HNF4A:hepatocyte nuclear factor 4 alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q13.12

Genomic location:

Preferred name:

NM_175914.5(HNF4A):c.340C>T (p.Arg114Trp)

Other names:

R127W; NM_175914.5(HNF4A):c.340C>T; p.Arg114Trp

HGVS:

NC_000020.11:g.44413714C>T
NG_009818.1:g.62914C>T
NM_000457.6:c.406C>T
NM_001030003.3:c.340C>T
NM_001030004.3:c.340C>T
NM_001258355.2:c.385C>T
NM_001287182.2:c.331C>T
NM_001287183.2:c.331C>T
NM_001287184.2:c.331C>T
NM_175914.5:c.340C>TMANE SELECT
NM_178849.3:c.406C>T
NM_178850.3:c.406C>T
NP_000448.3:p.Arg136Trp
NP_000448.3:p.Arg136Trp
NP_001025174.1:p.Arg114Trp
NP_001025175.1:p.Arg114Trp
NP_001245284.1:p.Arg129Trp
NP_001274111.1:p.Arg111Trp
NP_001274112.1:p.Arg111Trp
NP_001274113.1:p.Arg111Trp
NP_787110.2:p.Arg114Trp
NP_787110.2:p.Arg114Trp
NP_849180.1:p.Arg136Trp
NP_849181.1:p.Arg136Trp
LRG_483t1:c.340C>T
LRG_483t2:c.406C>T
LRG_483:g.62914C>T
LRG_483p1:p.Arg114Trp
LRG_483p2:p.Arg136Trp
NC_000020.10:g.43042354C>T
NM_000457.4:c.406C>T
NM_175914.3:c.340C>T
NM_175914.4:c.340C>T
P41235:p.Arg136Trp

Protein change:

R111W; ARG127TRP

Links:

UniProtKB: P41235#VAR_004668; OMIM: 600281.0003; dbSNP: rs137853336

NCBI 1000 Genomes Browser:

rs137853336

Molecular consequence:

NM_000457.6:c.406C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001030003.3:c.340C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001030004.3:c.340C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258355.2:c.385C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001287182.2:c.331C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001287183.2:c.331C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001287184.2:c.331C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_175914.5:c.340C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_178849.3:c.406C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_178850.3:c.406C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Maturity onset diabetes mellitus in young (MODY)
Synonyms:: Mason type diabetes
Identifiers:: MONDO: MONDO:0018911; MedGen: C0342276; Orphanet: 552; OMIM: 606391; Human Phenotype Ontology: HP:0004904

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002612745	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Jun 20, 2018)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10389854, 10606640, 10819248, 23485969, 23551881, 25414397, 27080136, 27486234, 9313765 Citation Link,
SCV004848510	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 15, 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

SCV002612745

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Jun 20, 2018)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV004848510

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 15, 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	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Functional characterization of the MODY1 gene mutations HNF4(R127W), HNF4(V255M), and HNF4(E276Q).

Navas MA, Munoz-Elias EJ, Kim J, Shih D, Stoffel M.

Diabetes. 1999 Jul;48(7):1459-65.

PubMed [citation]

PMID:: 10389854

Naturally occurring mutations in the human HNF4alpha gene impair the function of the transcription factor to a varying degree.

Lausen J, Thomas H, Lemm I, Bulman M, Borgschulze M, Lingott A, Hattersley AT, Ryffel GU.

Nucleic Acids Res. 2000 Jan 15;28(2):430-7.

PubMed [citation]

PMID:: 10606640
PMCID:: PMC102517

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV002612745.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

The p.R114W pathogenic mutation (also known as c.340C>T and R127W), located in coding exon 4 of the HNF4A gene, results from a C to T substitution at nucleotide position 340. The arginine at codon 114 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation was first reported in a Japanese maturity onset diabetes of the young (MODY) family (Furuta H et al. Diabetes, 1997 Oct;46:1652-7) and was subsequently reported in two Italian individuals with MODY (Delvecchio M et al. Diabetes Care, 2014 Dec;37:e258-60). This mutation has shown strong segregation with disease across multiple pedigrees; however, when compared to other mutations in HNF4A, reduced penetrance (54% vs. 71% by age 30), later age of onset (median 34 vs. 24, p=0.018), and decreased responsiveness to sulfonylurea treatment (48% vs. 73%, p = 0.038) were observed (Laver TW et al. Diabetes, 2016 Oct;65:3212-7). Although transactivation activity of this mutation was observed to be normal in one study (Navas MA et al. Diabetes, 1999 Jul;48:1459-65), additional studies using multiple conditions and additional cell lines have shown that DNA binding and transactivation ability is reduced by approximately 50% due to this mutation (Lausen J et al. Nucleic Acids Res., 2000 Jan;28:430-7; Yang Q et al. Diabetologia, 2000 Apr;43:520-4). Based on structural analysis, this alteration will disrupt proper dimerization of the receptor and DNA binding (Chandra V et al. Nature, 2013 Mar;495:394-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848510.1

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

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#	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: Apr 20, 2024

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