Submissions for variant NM_000545.8(HNF1A):c.686G>A (p.Arg229Gln)

dbSNP: rs1057520779

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222034	SCV002499521	pathogenic	Monogenic diabetes	2022-04-11	reviewed by expert panel	curation	The c.686G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 229 (p.(Arg229Gln)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.953, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies in both and positive C-peptide in one) (PP4_Moderate; PMID: 27913849). The c.686G>A variant was identified in 27 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 29927023, 28395978, 27913849, 9032114, 18513305, internal lab contributors). Functional studies demonstrated the p.Arg229Gln protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMIDs: 12530534, 12574234). Lastly, this variant segregated with diabetes, with at least 17 informative meioses in at more than three families with MODY (PP1_Strong; PMID: 18513305; internal lab contributors). In summary, c.686G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PS3_Supporting, PP1_strong, PS4, PM1_Supporting, PM2_Supporting, PP4_Moderate, PP3.
GeneDx	RCV000432234	SCV000517412	pathogenic	not provided	2024-04-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the variant damages normal HNF1A function (PMID: 12530534, 18513305); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9032114, 12453420, 18003757, 35327967, 12530534, 36208030, 31658956, 34789499, 36257325, 36227502, 36504295, 23624530, 27913849, 31754975, 37798422, 25414397, 18513305)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000432234	SCV002126559	pathogenic	not provided	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 229 of the HNF1A protein (p.Arg229Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity-onset diabetes of the young (PMID: 9032114, 25414397, 31754975; internal data). ClinVar contains an entry for this variant (Variation ID: 379904). 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 HNF1A protein function. Experimental studies have shown that this missense change affects HNF1A function (PMID: 12530534). For these reasons, this variant has been classified as Pathogenic.
Geisinger Clinic, Geisinger Health System	RCV002285329	SCV002562144	pathogenic	Maturity-onset diabetes of the young type 3	2022-08-02	criteria provided, single submitter	research	PS3_Supporting, PP1_Strong, PS4, PM1_Supporting, PM2, PP4_Moderate, PP3
Ambry Genetics	RCV002365490	SCV002665622	likely pathogenic	Maturity onset diabetes mellitus in young	2018-02-21	criteria provided, single submitter	clinical testing	The p.R229Q variant (also known as c.686G>A), located in coding exon 3 of the HNF1A gene, results from a G to A substitution at nucleotide position 686. The arginine at codon 229 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with maturity-onset diabetes of the young (Delvecchio M et al. Diabetes Care, 2014 Dec;37:e258-60; Irgens HU et al. Diabetologia, 2013 Jul;56:1512-9; Johansson BB et al. Diabetologia, 2017 04;60:625-635). Functional analysis in HeLa cells demonstrated reduce DNA binding affinity and transactivation activity compared to wild type (Thomas H et al. Biol. Chem., 2002 Nov;383:1691-700). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002285329	SCV005416726	pathogenic	Maturity-onset diabetes of the young type 3		criteria provided, single submitter	clinical testing	PM2_Supporting+PM5_Strong+PP3_Strong+PS4+PP1_Strong
PreventionGenetics, part of Exact Sciences	RCV003983038	SCV004800461	pathogenic	HNF1A-related disorder	2024-06-19	no assertion criteria provided	clinical testing	The HNF1A c.686G>A variant is predicted to result in the amino acid substitution p.Arg229Gln. This variant has been reported in multiple individuals with maturity-onset diabetes of the young (MODY) (Kaisaki et al. 1997. PubMed ID: 9032114; Eide et al. 2008. PubMed ID: 18513305: Irgens et al. 2013. PubMed ID: 23624530; Delvecchio et al. 2014. PubMed ID: 25414397; Li et al. 2019. PubMed ID: 31658956; Fu et al. 2019. PubMed ID: 31754975). In vitro functional studies demonstrate that expression of this variant results in decreased transactivation potential, impaired DNA binding ability (Thomas et al. 2002. PubMed ID: 12530534) and subcellular mislocalization (Bjørkhaug et al. 2003. PubMed ID: 12574234). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as pathogenic by the ClinGen monogenic diabetes variant curation expert panel (VCEP, https://www.ncbi.nlm.nih.gov/clinvar/variation/379904/). Additionally, different missense changes impacting the same amino acid (p.Arg229Pro and p.Arg229Gly) have also been reported in individuals with MODY (Ellard et al. 2000. PubMed ID: 11058894; Colclough et al. 2013. PubMed ID: 23348805). Taken together the c.686G>A (p.Arg229Gln) variant is interpreted as pathogenic.