rs1555813319
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM5_SupportingPP4_ModeratePP3PM2_SupportingPS4PP1_Strong
This summary comes from the ClinGen Evidence Repository: The c.200G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 67 (p.(Arg67Gln)) of NM_175914.5. This variant has poor data quality in gnomAD v2.1.1 exomes but is absent in gnomAD genomes v3.0 and therefore at the discretion of the ClinGen MDEP PM2_Supporting will be applied (PM2_Supporting). This variant was identified in 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:31523701, 20705777, 21353246, 29493090, internal lab contributors). At least 3 of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID:20705777, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with at least 10 informative meioses in five families (PP1_Strong; PMID:20705777, internal lab contributor). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Another missense variant, c.199C>T (p.(Arg67Trp)), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg67Gln) (PM5_Supporting). In summary, the c.200G>A variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PS4, PP4_Moderate, PM1, PP3, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409103974/MONDO:0015967/085
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
HNF4A
NM_175914.5 missense
NM_175914.5 missense
Scores
13
3
3
Clinical Significance
Conservation
PhyloP100: 9.92
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM5
For more information check the summary or visit ClinGen Evidence Repository.
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.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461428Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727020
GnomAD4 exome
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4
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1461428
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33
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2
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727020
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 30, 2024 | This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant appears to segregate with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant is also referred to as p.R80Q or p.R67Q in published literature. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 06, 2024 | The HNF4A c.200G>A; p.Arg67Gln variant (rs1555813319, ClinVar Variation ID: 435436), also known as Arg80Gln in traditional nomenclature and Arg89Gln for NM_000457, is reported in the literature in individuals affected with diabetes and maturity-onset diabetes of the young (Colclough 2022, Forlani 2010, Gordon 2019, Mirshahi 2022, Park 2019, Pingul 2011, Tung 2018). This variant was also found to segregate with disease in two families (Forlani 2010, Pingul 2011). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism, but is considered a low confidence variant in the database. Computational analyses predict that this variant is deleterious (REVEL: 0.943). Based on available information, the p.Arg67Gln variant is considered to be pathogenic. References: Colclough K et al. Syndromic Monogenic Diabetes Genes Should Be Tested in Patients With a Clinical Suspicion of Maturity-Onset Diabetes of the Young. Diabetes. 2022 Mar 1;71(3):530-537. PMID: 34789499. Forlani G et al. Double heterozygous mutations involving both HNF1A/MODY3 and HNF4A/MODY1 genes: a case report. Diabetes Care. 2010 Nov;33(11):2336-8. PMID: 20705777. Gordon K et al. A Case of a 13-Year-Old Female With Maturity Onset Diabetes of the Young (MODY) Identified by School-Based Cardiovascular Screening. Glob Pediatr Health. 2019 Sep 5;6:2333794X19874215. PMID: 31523701. Mirshahi UL et al. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. PMID: 36257325. Park SS et al. Identifying Pathogenic Variants of Monogenic Diabetes Using Targeted Panel Sequencing in an East Asian Population. J Clin Endocrinol Metab. 2019 Sep 1;104(9):4188-4198. PMID: 30977832. Pingul MM et al. Hepatocyte nuclear factor 4a gene mutation associated with familial neonatal hyperinsulinism and maturity-onset diabetes of the young. J Pediatr. 2011 May;158(5):852-4. PMID: 21353246. Tung JY et al. Clinical heterogeneity of hyperinsulinism due to HNF1A and HNF4A mutations. Pediatr Diabetes. 2018 Aug;19(5):910-916. PMID: 29493090. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 31, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 67 of the HNF4A protein (p.Arg67Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with HNF4A-related conditions (PMID: 20705777, 21353246, 29493090, 30977832). It has also been observed to segregate with disease in related individuals. This variant is also known as c.239g>a (p.Arg80Gln), p.Arg89Gln. ClinVar contains an entry for this variant (Variation ID: 435436). 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. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 27, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.R80Q and p.R89Q; This variant is associated with the following publications: (PMID: 31523701, 30977832, 36208030, 29493090, 34789499, 21353246, 36257325, 20705777, 22662265, 18829458) - |
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
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 02, 2024 | - - |
Maturity onset diabetes mellitus in young Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 17, 2025 | Variant summary: HNF4A c.200G>A (p.Arg67Gln) results in a conservative amino acid change located in the Zinc finger, nuclear hormone receptor-type domain (IPR001628) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.200G>A (also known as p.R80Q) has been reported in the literature in multiple individuals affected with neonatal hyperinsulinism, macrosomia, and diabetes (examples: Forlani_2010, Pingul_2011 and Johannsson_2012). These data indicate that the variant is very likely to be associated with disease. Another variant affecting the same amino acid (p.R67W) is associated with MODY in HGMD. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34789499, 20705777, 22662265, 21353246). ClinVar contains an entry for this variant (Variation ID: 435436). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hyperinsulinism due to HNF4A deficiency Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 22, 2015 | - - |
Monogenic diabetes Pathogenic:1
| Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Apr 05, 2024 | The c.200G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 67 (p.(Arg67Gln)) of NM_175914.5. This variant has poor data quality in gnomAD v2.1.1 exomes but is absent in gnomAD genomes v3.0 and therefore at the discretion of the ClinGen MDEP PM2_Supporting will be applied (PM2_Supporting). This variant was identified in 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:31523701, 20705777, 21353246, 29493090, internal lab contributors). At least 3 of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID:20705777, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with at least 10 informative meioses in five families (PP1_Strong; PMID:20705777, internal lab contributor). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It resides in an amino acid within the HNF4alpha DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Another missense variant, c.199C>T (p.(Arg67Trp)), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg67Gln) (PM5_Supporting). In summary, the c.200G>A variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PS4, PP4_Moderate, PM1, PP3, PM2_Supporting, PM5_Supporting. - |
Maturity-onset diabetes of the young type 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Geisinger Clinic, Geisinger Health System | Aug 02, 2022 | PS4, PM2, PP3, PP1_Strong, PP4_Moderate, PM1, PM5_Supporting - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
.;.;.;T;D;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
.;.;.;.;.;L;L;L
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;D;.;.;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;.;.;D;D;D
Sift4G
Pathogenic
D;D;D;D;T;D;D;D
Polyphen
1.0, 1.0
.;D;D;.;.;D;D;.
Vest4
MutPred
0.81
.;.;.;.;.;Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);
MVP
MPC
1.5
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at