Submissions for variant NM_175914.5(HNF4A):c.1321A>G (p.Ile441Val)

gnomAD frequency: 0.00061  dbSNP: rs147638455

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003234540	SCV003932661	benign	Monogenic diabetes	2023-05-27	reviewed by expert panel	curation	The c.1321A>G p.(Ile441Val) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005025, which is greater than the MDEP threshold for BA1 (BA1). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and GAD negative) (PP4_Moderate, internal contributors). There is evidence in vitro that this variant has identical transactivation activity to wildtype, indicating that this variant does not impact protein function (BS3_Supporting, PMID: 30191603). This variant does not segregate with diabetes in three families (BS4; internal lab contributors, PMIDs: 25905084, 10227563, 33324081). This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1321A>G p.(Ile441Val) meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): BA1, PP4_Moderate, BS3_Supporting, BS4, BP5.
Eurofins Ntd Llc (ga)	RCV000725499	SCV000337348	uncertain significance	not provided	2015-11-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000725499	SCV000589599	likely benign	not provided	2021-05-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23227446, 27884173, 24097065, 25905084, 26059258, 10227563, 21105491, 10768098, 31264968, 31595705)
Fulgent Genetics, Fulgent Genetics	RCV000764241	SCV000895244	uncertain significance	Maturity-onset diabetes of the young type 1; Type 2 diabetes mellitus; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000030015	SCV001302393	uncertain significance	Maturity-onset diabetes of the young type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001142000	SCV001302394	uncertain significance	Familial hyperinsulinism	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Athena Diagnostics Inc	RCV000725499	SCV001475904	likely benign	not provided	2019-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358754	SCV001554611	likely benign	not specified	2021-03-30	criteria provided, single submitter	clinical testing	Variant summary: HNF4A c.1321A>G (p.Ile441Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251452 control chromosomes, predominantly at a frequency of 0.00072 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 230 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1321A>G has been reported in the literature (example: deSantana_2019, Majidi_2018). These reports however, do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes of the Young 1/Neonatal Diabetes Mellitus. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Guo_2019). Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=1) or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000725499	SCV001747309	benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	HNF4A: BS1, BS2
Genetic Services Laboratory, University of Chicago	RCV001358754	SCV002067858	likely benign	not specified	2021-11-04	criteria provided, single submitter	clinical testing
Invitae	RCV000725499	SCV002293203	uncertain significance	not provided	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 441 of the HNF4A protein (p.Ile441Val). This variant is present in population databases (rs147638455, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 10227563, 21105491, 23247789, 26059258, 31595705, 33846082, 34373539, 35256061). This variant is also known as p.Ile454Val, p.Ile463Val. ClinVar contains an entry for this variant (Variation ID: 36345). Advanced 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 at Invitae 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV000725499	SCV002503561	uncertain significance	not provided	2021-02-21	criteria provided, single submitter	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844803	SCV001877068	uncertain significance	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research