Submissions for variant NM_000545.8(HNF1A):c.607C>T (p.Arg203Cys)

dbSNP: rs1180119907

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222075	SCV002499515	pathogenic	Monogenic diabetes	2022-04-10	reviewed by expert panel	curation	The c.607C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to cysteine at codon 203 (p.(Arg203Cys)) of NM_000545.8. This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture highly consistent with HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea-responsive) (internal lab contributors). (PS2; internal lab contributors). Additionally, this variant was identified in eight unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs:15928245, 10078571, 18811724,20393147,23517481, internal lab contributors). The c.607C>T 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 was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive or antibody negative (PP4_Moderate; internal lab contributors). Another missense variant, c.608G>A (p.Arg203His) has been interpreted as pathogenic by the ClinGen MDEP, and p. Arg203Cys has a greater Grantham distance (PM5). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.91, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant segregated with diabetes, with at least five informative meioses in three families with MODY (PP1_Strong; PMID:18811724; internal lab contributors). Functional studies demonstrated the p.Arg203Cys protein has transactivation 53% of wildtype; however, this is between the ClinGen MDEP cutoffs for PS3_Supporting and BS3_Supporting (PMID: 15522234). In summary, c.607C>T 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): PS2, PS4, PM1, PM2_Supporting, PP4_Moderate, PM5, PP3, PP1_Strong.
Genetic Services Laboratory, University of Chicago	RCV001817752	SCV002069127	pathogenic	not provided	2018-03-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001817752	SCV002197132	pathogenic	not provided	2024-08-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 203 of the HNF1A protein (p.Arg203Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of maturity-onset diabetes of the young (PMID: 10078571, 31363388). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1338381). 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: 10078571). 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; 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.
GeneDx	RCV001817752	SCV003837148	pathogenic	not provided	2022-09-12	criteria provided, single submitter	clinical testing	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; This variant is associated with the following publications: (PMID: 28410371, 23517481, 33950347, 32684311, 31363388, 21168233, 20393147, 10078571, 11058894, 15928245, 18811724, 25418671, 34789499, 12453420, 18003757)
Ambry Genetics	RCV003339756	SCV004057997	likely pathogenic	Maturity onset diabetes mellitus in young	2023-06-26	criteria provided, single submitter	clinical testing	The p.R203C variant (also known as c.607C>T), located in coding exon 3 of the HNF1A gene, results from a C to T substitution at nucleotide position 607. The arginine at codon 203 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in several individuals with non-insulin dependent diabetes or suspected diagnosis of maturity-onset diabetes of the young (MODY), including three affected individuals across multiple generations in one family (Yamada S et al. Diabetes, 1999 Mar;48:645-8; Horikawa Y et al. Diabet Med, 2014 Jun;31:721-7; Plengvidhya N et al. World J Diabetes, 2019 Jul;10:414-420). In one study, this variant demonstrated lower activity and transactivation activity in Caco2 cells (Gu N et al. Biochem Biophys Res Commun, 2004 Dec;325:308-13); however, in Min6 cells, this variant demonstrated decreased activity at lower concentrations and higher activity than wildtype with increased levels of transfected DNA (Yamada S et al. Diabetes, 1999 Mar;48:645-8). In another study, protein with this variant was predominantly located in the cytoplasm while wildtype protein was distributed in the nucleus (Sujjitjoon J et al. Biochem Biophys Res Commun, 2020 Aug;529:826-833). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Two other alterations at the same codon, p.R203S (c.607C>A) and p.R203H (c.608G>A), have been described in individuals with MODY (Alvelos MI et al. J Clin Med, 2020 Jan;9; Colclough K et al. Hum Mutat, 2013 May;34:669-85; Johansson BB et al. Diabetologia, 2017 Apr;60:625-635; Thanabalasingham G et al. Diabetes, 2013 Apr;62:1329-37). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003339756	SCV005202630	pathogenic	Maturity onset diabetes mellitus in young	2024-07-11	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.607C>T (p.Arg203Cys) results in a non-conservative amino acid change located in the Homeodomain (IPR001356) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251554 control chromosomes. c.607C>T has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 3 (e.g. Yamada_1999, Johansen_2005, Plengvidhya_2008). Additionally, other missense variants affecting the same codon (p.Arg203Leu, p.Arg203Ser, p.Arg203His) have been classified on the pathogenic spectrum in ClinVar. These data indicate that the variant is very likely to be associated with disease. Two publications report experimental evidence evaluating an impact on protein function, indicating a change in protein function (e.g. Yamada_1999, Bjorkhaug_2005). The following publications have been ascertained in the context of this evaluation (PMID: 10078571, 15928245, 12488962, 12488961, 16496320, 16274290, 15726414, 17924661, 18811724). ClinVar contains an entry for this variant (Variation ID: 1338381). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004753394	SCV005348647	pathogenic	HNF1A-related disorder	2024-04-09	no assertion criteria provided	clinical testing	The HNF1A c.607C>T variant is predicted to result in the amino acid substitution p.Arg203Cys. This variant has been reported in individuals with maturity-onset diabetes of the young (MODY, Yamada et al. 1999. PubMed ID: 10078571; Lopez et al. 2010. PubMed ID: 21168233; Santos Monteiro et al. 2022. PubMed ID: 36208343). One study demonstrated this variant segregating with disease (Figure 1a, Plengvidhya et al. 2008. PubMed ID: 18811724). In vitro functional studies demonstrate that expression of this variant affects nuclear translocation, cell growth, and transactivation activity (Yamada et al. 1999. PubMed ID: 10078571; Gu et al. 2004. PubMed ID: 15522234; Sujjitjoon et al. 2020. PubMed ID: 32684311). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD, and has been classified as pathogenic by a ClinGen variant curation expert panel (VCEP) for monogenic diabetes (https://www.ncbi.nlm.nih.gov/clinvar/variation/1338381/). Additionally, different missense changes impacting the same amino acid (p.Arg203Ser, p.Arg203His, and p.Arg203Gly) have been reported in individuals with MODY (Table S1, Colclough et al. 2013. PubMed ID: 23348805; Lopez et al. 2011. PubMed ID: 21168233). Taken together, this variant is interpreted as pathogenic.