Submissions for variant NM_175914.5(HNF4A):c.724G>A (p.Val242Met)

gnomAD frequency: 0.00019  dbSNP: rs139779712

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001174367	SCV005367840	benign	Monogenic diabetes	2024-09-18	reviewed by expert panel	curation	The c.724G>A variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of valine to methionine at codon 242(p.(Val242Met)) of NM_175914.5. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0003423, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.81, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies performed on this variant showed transactivation activity >= 75% of that of wildtype, providing evidence that the variant does not affect HNF4A function (BS3_Supporting; PMIDs: 15728204, 10666040, 10389854). In summary, c.724G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BA1, PP3, BS3_Supporting.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174367	SCV001337505	uncertain significance	Monogenic diabetes	2018-01-19	criteria provided, single submitter	research	ACMG criteria: PP3 (9 predictors), BS3 (PMID: 10389854 and 10606640)=VUS
GeneDx	RCV002284467	SCV002574656	uncertain significance	not provided	2022-06-21	criteria provided, single submitter	clinical testing	Reported in unrelated patients with type 1 or type 2 diabetes (Elk et al., 2005; Jafar-Mohammadi et al., 2011; Johnson et al., 2019; Yu et al., 2019) in published literature as well as reported as a polymorphism (Anuradha et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15728204, 9267996, 10606640, 10389854, 34805638, 20878384, 24097065, 26552609, 30191644, 31264968, 32041611, 21062274)
Fulgent Genetics, Fulgent Genetics	RCV002491490	SCV002796976	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	2022-03-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002284467	SCV003296554	uncertain significance	not provided	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 242 of the HNF4A protein (p.Val242Met). This variant is present in population databases (rs139779712, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (PMID: 9267996, 21062274, 24097065, 30191644, 31264968, 32041611). This variant is also known as Val/Met255, p.Val264Met and p.V239M. ClinVar contains an entry for this variant (Variation ID: 917409). 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. Experimental studies have shown that this missense change affects HNF4A function (PMID: 10606640, 15728204). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587061	SCV005076060	uncertain significance	not specified	2024-04-26	criteria provided, single submitter	clinical testing	Variant summary: HNF4A c.724G>A (p.Val242Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251458 control chromosomes, predominantly at a frequency of 0.00044 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 141-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 Non-Finnish European origin. c.724G>A has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus without strong evidence of causality (e.g. Moller_1997, Flannick_2013). These reports do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus. Publications report experimental evidence evaluating an impact on protein function (Lausen_2000, Ek_2005). One of these studies found that the variant results in 76% of normal transactivation activity. The following publications have been ascertained in the context of this evaluation (PMID: 9267996, 10606640, 15728204, 24097065, 30191644, 31264968). ClinVar contains an entry for this variant (Variation ID: 917409). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV003319445	SCV004024124	likely pathogenic	Maturity-onset diabetes of the young type 1		no assertion criteria provided	research