20-44413714-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received -3 ACMG points: 6P and 9B. PP3PP4BS2PP1_StrongBP5BS1

This summary comes from the ClinGen Evidence Repository: The c.340C>T variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 114 (p.(Arg114Trp)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.919, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000074, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant was identified in over 80 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID:27486234, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes, with 31 informative meioses (PP1_Strong; internal lab contributors). This variant was identified in at least 3 nondiabetic individuals >70 years old, and the expected penetrance for HNF4A-monogenic diabetes is 95% by age 70 (BS2; PMID:9313765. internal lab contributors) (BS2). This variant was identified in five individuals with an alternate molecular basis for disease, including two siblings with the HNF1A variant NM_000545.8:c872dup (p.Gly292fs*25) (BP5; PMID:2351881, internal lab contributors). This variant has previously been considered to be pathogenic for a low penetrance form of MODY, and reporting has been of clinical utility for considering treatment with sulfonylureas, which have ~48% effectiveness in individuals with this variant (PMID:27486234). In summary, c.340C>T meets phenotype, segregation, and computational criteria to be classified as likely pathogenic. While adding its population frequency, penetrance, and co-occurrence (which may have synergistic impact) criteria would lead to a likely benign classification, the MDEP consensus is that this should be considered a reportable likely pathogenic variant with reduced penetrance that may respond to sulfonylurea treatment. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BS1, BS2, PP1_Strong, BP5, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120206/MONDO:0015967/085

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 2.50

Publications

39 publications found

Variant links:

Genes affected

HNF4A (HGNC:5024): (hepatocyte nuclear factor 4 alpha) The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]

HNF4A Gene-Disease associations (from GenCC):

maturity-onset diabetes of the young type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
monogenic diabetes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
hyperinsulinism due to HNF4A deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HNF4A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received -3 ACMG points.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5 link	c.340C>T	p.Arg114Trp	missense_variant	Exon 4 of 10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9 link	c.340C>T	p.Arg114Trp	missense_variant	Exon 4 of 10	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000797

AC:

AN:

250910

AF XY:

0.0000664

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000120

AC:

176

AN:

1461616

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.000134

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000149

AC:

166

AN:

1111844

Other (OTH)

AF:

0.0000662

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151998

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41388

American (AMR)

AF:

0.000197

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000208

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000604

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Feb 16, 2018

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 114 of the HNF4A protein (p.Arg114Trp). This variant is present in population databases (rs137853336, gnomAD 0.01%). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 9313765, 11043869, 15830177, 25414397, 27486234, 29207974, 30977832; internal data). It has also been observed to segregate with disease in related individuals. Of note, this variant has been observed to have reduced penetrance, with later average age of onset and decreased responsiveness to sulfonylurea treatment when compared to other HNF4A mutations (PMID: 27486234). This variant is also known as p.Arg127Trp or p.Arg136Trp. ClinVar contains an entry for this variant (Variation ID: 9212). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF4A protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HNF4A function (PMID: 10389854, 10606640, 10819248, 16223942). For these reasons, this variant has been classified as Pathogenic.

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 03, 2024

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant associates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function, however the effect seen in these assays was less severe than for known pathogenic variants in this gene (PMID: 10606640, 10819248). This variant is also referred to as R127W and R114W in published literature.

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 22, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Considered to be a likely pathogenic variant with reduced penetrance that may respond to sulfonylurea treatment by the ClinGen Monogenic Diabetes Expert Panel (ClinVar SCV#004174222.1); Published functional studies show wild-type target gene activation is retained, however, abnormal transcriptional activation and altered activity during indirect target gene regulation occurs (PMID: 16223942); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R127W and R136W; This variant is associated with the following publications: (PMID: 15830177, 29377200, 34662886, 11272211, 10819248, 11043869, 17407387, 24097065, 23551881, 27486234, 10606640, 29207974, 10389854, 30665703, 29998026, 29734081, 31281738, 9313765, 30191644, 30977832, 27271189, 26287533, 24843605, 15752752, 23485969, 40715678, 34789499, 36257325, 25414397, 16223942, 35325889, 35460704, 36227502, 34362814, 39379762, 37808701, 38855865, 25306193, 32041611)

Maturity onset diabetes mellitus in young

Pathogenic:3

Mar 15, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory

Aug 20, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.340C>T (p.R114W) alteration is located in exon 4 (coding exon 4) of the HNF4A gene. This alteration results from a C to T substitution at nucleotide position 340, causing the arginine (R) at amino acid position 114 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.008% (20/250910) total alleles studied. The highest observed frequency was 0.015% (5/34564) of Latino alleles. This variant, also referred to as R127W and R136W in the literature, was identified in one or more individuals with features consistent with HNF4A-related maturity onset diabetes of the young and segregated with disease in at least one family (Furuta, 1997; Delvecchio, 2014; Laver, 2016). However, when compared to other pathogenic variants in HNF4A, this variant has reduced penetrance, later age of onset, and decreased responsiveness to sulfonylurea treatment (Laver, 2016). In addition, in one or more case control studies, this variant was found to be associated with an increased risk of type II diabetes (Huerta-Chagoya, 2024). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing HNF4A function, this variant showed functionally abnormal results; however, in another assay, this variant showed a functionally normal result (Navas, 1999; Lausen, 2000; Yang, 2000). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

May 23, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HNF4A c.340C>T (p.Arg114Trp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 8e-05 in 250910 control chromosomes. The observed variant frequency is approximately 25.51 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF4A causing Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus phenotype (3.1e-06). c.340C>T has been widely reported in the literature in the heterozygous state in numerous individuals affected with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus, with notably reduced penetrance (Furuta_1997, Laver_2016, Shi Park_2019, Wright_2019, Shankar_2013). Further, the ClinGen Monogenic Diabetes Expert Panel has noted >30 informative meioses demonstrating segregation of this variant with diabetes (ClinVar) and Wright_2019 found a statistically significant association (OR 2.9, 95% CI [1.7, 5] and p. value 3*10^-4) with diabetes across >500,000 individuals in the British population. These data indicate that the variant is likely to be associated with disease. At least two publications reporting conflicting experimental evidence evaluating an impact on protein function were ascertained. One study reports 30%-50% of normal transactivation potential (Lausen_2000) while the other reports transactivation at levels identical to the wild-type control (Navas_1999). The following publications have been ascertained in the context of this evaluation (PMID: 29207974, 25414397, 24097065, 9313765, 30191644, 10606640, 27486234, 10389854, 15830177, 23551881, 30977832, 30665703, 10819248). ClinVar contains an entry for this variant (Variation ID: 9212). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Maturity-onset diabetes of the young type 1

Pathogenic:2

Oct 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Dec 05, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Likely pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.001 for a dominant condition (v4: 186 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by the ClinGen Monogenic Diabetes Variant Curation Expert Panel (ClinVar). Additional information: Variant is predicted to result in a missense amino acid change from arginine to tryptophan; This variant is heterozygous; This gene is associated with autosomal dominant disease. Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young (MIM#616026) is associated with a single recurring missense variant (PMID: 20164212); Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4) (highest allele count: 96 heterozygotes, 0 homozygotes); Loss of function and dominant negative are known mechanisms of disease in this gene. Loss of function through a reduction of DNA binding is associated with MODY, type I (MIM#125850) and diabetes mellitus, noninsulin-dependent (MIM#125853) (OMIM; PMID: 31875549). Dominant negative is associated with Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young (MIM#616026) (PMID: 31875549); The condition associated with this gene has incomplete penetrance (PMID: 36257325); This variant has been shown to be paternally inherited (by trio analysis).

Type 2 diabetes mellitus;C1852093:Maturity-onset diabetes of the young type 1;C4014962:Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young

Pathogenic:1

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Monogenic diabetes

Pathogenic:1

Dec 02, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.340C>T variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 114 (p.(Arg114Trp)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.919, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000074, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant was identified in over 80 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 27486234, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes, with 31 informative meioses (PP1_Strong; internal lab contributors). This variant was identified in at least 3 nondiabetic individuals >70 years old, and the expected penetrance for HNF4A-monogenic diabetes is 95% by age 70 (BS2; PMID: 9313765. internal lab contributors) (BS2). This variant was identified in five individuals with an alternate molecular basis for disease, including two siblings with the HNF1A variant NM_000545.8:c872dup (p.Gly292fs*25) (BP5; PMID: 2351881, internal lab contributors). This variant has previously been considered to be pathogenic for a low penetrance form of MODY, and reporting has been of clinical utility for considering treatment with sulfonylureas, which have ~48% effectiveness in individuals with this variant (PMID: 27486234). In summary, c.340C>T meets phenotype, segregation, and computational criteria to be classified as likely pathogenic. While adding its population frequency, penetrance, and co-occurrence (which may have synergistic impact) criteria would lead to a likely benign classification, the MDEP consensus is that this should be considered a reportable likely pathogenic variant with reduced penetrance that may respond to sulfonylurea treatment. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BS1, BS2, PP1_Strong, BP5, PP3, PP4.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0

.;.;.;D;.;D;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.0

.;.;.;.;M;M;M

PhyloP100

2.5

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.3

D;.;D;.;D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;.;D;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D

Vest4

0.84

ClinPred

0.67

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.87

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over