Submissions for variant NM_000545.8(HNF1A):c.608G>A (p.Arg203His)

gnomAD frequency: 0.00001  dbSNP: rs587780357

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222019	SCV002499516	pathogenic	Monogenic diabetes	2022-04-10	reviewed by expert panel	curation	The c.608G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 203 (p.(Arg203His)) of NM_000545.8. This variant segregated with diabetes, in more than 10 families with MODY (PP1_Strong; internal lab contributors). Additionally, this variant was identified in at least 15 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 23348805, 27913849, internal lab contributors). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.958, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Arg203His protein has abnormal nuclear localization below 40% of wildtype, indicating that this variant impacts protein function (PMID: 32910913) (PS3_Supporting). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; PMID:27913849). In summary, c.608G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PS4, PP1_Strong, PM1, PM2_Supporting, PP4_Moderate,PP3, PS3_Supporting.
GeneDx	RCV000430669	SCV000521027	pathogenic	not provided	2024-09-03	criteria provided, single submitter	clinical testing	A different missense change at this residue (p.(R203C)) has been reported as pathogenic in the published literature and at GeneDx in association with MODY (PMID: 31363388, 21168233); 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; Classified as pathogenic by the ClinGen Monogenic Diabetes Expert Panel (ClinVar SCV002499516.1); This variant is associated with the following publications: (PMID: 18003757, 12488961, 15657605, 11772903, 23274891, 16274290, 15928245, 27271189, 23348805, 12453420, 10588527, 12627330, 30293189, 35472491, 34789499, 36836406, 36227502, 33046911, 32910913, 33950347, 35673428, 36257325, 33477506, 35921062, 27913849, 31363388, 21168233)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000430669	SCV002199768	pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 203 of the HNF1A protein (p.Arg203His). This variant is present in population databases (rs587780357, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of maturity-onset diabetes of the young (PMID: 10588527, 12627330, 15928245, 30293189). ClinVar contains an entry for this variant (Variation ID: 129235). 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 HNF1A protein function. Experimental studies have shown that this missense change affects HNF1A function (PMID: 16274290). This variant disrupts the p.Arg203 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21168233, 30293189, 31363388; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Geisinger Clinic, Geisinger Health System	RCV002285267	SCV002562141	pathogenic	Maturity-onset diabetes of the young type 3	2022-08-02	criteria provided, single submitter	research	PS4, PP1_Strong, PM1, PM2, PP4_Moderate, PP3, PS3_Supporting
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002354301	SCV002605467	pathogenic	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs587780357 with MODY3.
Ambry Genetics	RCV002354301	SCV002656280	likely pathogenic	Maturity onset diabetes mellitus in young	2021-04-07	criteria provided, single submitter	clinical testing	The p.R203H variant (also known as c.608G>A), located in coding exon 3 of the HNF1A gene, results from a G to A substitution at nucleotide position 608. The arginine at codon 203 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in multiple individuals and families with features of maturity-onset diabetes of the young (Thanabalasingham G et al. Diabetes, 2013 Apr;62:1329-37; Shepherd M et al. Diabetes Care, 2016 Nov;39:1879-1888; Bansal V et al. BMC Med, 2017 12;15:213; Johansson BB et al. Diabetologia, 2017 04;60:625-635; Bonnefond A et al. Nat Metab, 2020 10;2:1126-1134; Ivanoshchuk DE et al. J Pers Med, 2021 Jan;11:). Based on internal structural analysis, this variant is mildly destabilizing to the local structure (Chi YI et al. Mol Cell, 2002 Nov;10:1129-37; P S et al. PLoS One, 2017 Apr;12:e0174953). 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.
Athena Diagnostics	RCV000430669	SCV002770449	pathogenic	not provided	2022-07-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with MODY. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant is located in a region that is considered important for protein function and/or structure.
Genetic Services Laboratory, University of Chicago	RCV000117232	SCV002070469	likely pathogenic	Diabetes mellitus type 1	2017-08-23	no assertion criteria provided	clinical testing	DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.608G>A, in exon 3 that results in an amino acid change, p.Arg203His. The p.Arg203His change affects a highly conserved amino acid residue located in a domain of the HNF1A protein that is known to be functional. The p.Arg203His substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). The p.Arg203His amino acid change has been described in the literature in one patient with early-onset diabetes (Ng et al., 1999. Diabet Med 16:956-63). In addition, different pathogenic sequence changes affecting the same amino acid residue (p.Arg203) has been described in patients with HNF1A-related maturity-onset diabetes of the young (MODY) (Lopez et al., 2011. Diabetes Res Clin Pract 91:208-12; Colclough et al., 2013. Hum Mutat 34:669-85; Yamada et al., 1999. Diabetes 48: 645-8).
PreventionGenetics, part of Exact Sciences	RCV004752747	SCV005362210	pathogenic	HNF1A-related disorder	2024-02-29	no assertion criteria provided	clinical testing	The HNF1A c.608G>A variant is predicted to result in the amino acid substitution p.Arg203His. This variant has been reported in several individuals with maturity-onset diabetes of the young (MODY) (see examples: Ng et al. 1999. PubMed ID: 10588527; Wang et al. 2018. PubMed ID: 30293189; Ma et al. 2020. PubMed ID: 32238361; Thanabalasingham et al. 2012. PubMed ID: 23274891; Wang DW et al 2022. PubMed ID: 35921062). In vitro functional studies demonstrate that expression of this variant results in protein mislocalization and reduced DNA binding ability compared to wild-type (Bjørkhaug L et al 2005. PubMed ID: 16274290; Figure S5, Althari et al. 2020. PubMed ID: 32910913). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. 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/129235/). Additionally, different missense changes impacting the same amino acid (p.Arg203Ser, p.Arg203Gly, p.Arg203Cys) have been reported in individuals with MODY (Colclough et al. 2013. PubMed ID: 23348805; Lopez et al. 2011. PubMed ID: 21168233). Taken together, the c.608G>A (p.Arg205His) variant is interpreted as pathogenic.