NM_000545.8:c.608G>A
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS4PP1_StrongPS3_SupportingPP4_ModeratePP3PM2_SupportingPM1
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA153100/MONDO:0015967/017
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| HNF1A | NM_000545.8 | c.608G>A | p.Arg203His | missense_variant | Exon 3 of 10 | ENST00000257555.11 | NP_000536.6 | |
| HNF1A | NM_001306179.2 | c.608G>A | p.Arg203His | missense_variant | Exon 3 of 10 | NP_001293108.2 | ||
| HNF1A | NM_001406915.1 | c.608G>A | p.Arg203His | missense_variant | Exon 3 of 9 | NP_001393844.1 | ||
| HNF1A | XM_024449168.2 | c.608G>A | p.Arg203His | missense_variant | Exon 3 of 9 | XP_024304936.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| HNF1A | ENST00000257555.11 | c.608G>A | p.Arg203His | missense_variant | Exon 3 of 10 | 1 | NM_000545.8 | ENSP00000257555.5 |
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251318Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135870
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461880Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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. -
The HNF1A c.608G>A;p.Arg203His variant (rs587780357, ClinVar Variation ID 129235) is reported in the literature in multiple individuals affected with monogenic diabetes (Ivanoshchuk 2023, Mirshahi 2022, Svalastoga 2023, Tsoi 2024, Wang 2022). This variant is only observed on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Arg203Cys, Arg203Gly, and Arg203Ser) have also been reported in individuals with monogenic diabetes (Lopez 2011, Mirshahi 2022, Santos Monteiro 2023). Functional analyses of the variant protein show reduced DNA binding and decreased transactivation by Arg203His variant (Althari 2020). Computational analyses predict that this variant is deleterious (REVEL: 0.958). Based on available information, this variant is considered to be pathogenic. References: Althari S et al. Unsupervised Clustering of Missense Variants in HNF1A Using Multidimensional Functional Data Aids Clinical Interpretation. Am J Hum Genet. 2020 Oct 1. PMID: 32910913. Ivanoshchuk D et al. The Mutation Spectrum of Rare Variants in the Gene of Adenosine Triphosphate (ATP)-Binding Cassette Subfamily C Member 8 in Patients with a MODY Phenotype in Western Siberia. J Pers Med. 2023 Jan 19. PMID: 36836406. Lopez AP et al. HNF1 alpha gene coding regions mutations screening, in a Caucasian population clinically characterized as MODY from Argentina. Diabetes Res Clin Pract. 2011 Feb. PMID: 21168233. Mirshahi UL et al. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. Am J Hum Genet. 2022 Nov 3. PMID: 36257325. Santos Monteiro S et al. Maturity-onset diabetes of the young in a large Portuguese cohort. Acta Diabetol. 2023 Jan. PMID: 36208343. Svalastoga P et al. Characterisation of HNF1A variants in paediatric diabetes in Norway using functional and clinical investigations to unmask phenotype and monogenic diabetes. Diabetologia. 2023 Dec. PMID: 37798422. Tsoi STF et al. Monogenic diabetes in a Chinese population with young-onset diabetes: A 17-year prospective follow-up study in Hong Kong. Diabetes Metab Res Rev. 2024 Jul. PMID: 38821874. Wang DW et al. Early-onset diabetes involving three consecutive generations had different clinical features from age-matched type 2 diabetes without a family history in China. Endocrine. 2022 Oct. PMID: 35921062. -
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) -
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. -
Maturity onset diabetes mellitus in young Pathogenic:3
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. -
Variant summary: HNF1A c.608G>A (p.Arg203His) 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 8e-06 in 251318 control chromosomes (gnomAD). c.608G>A has been reported in the literature in individuals affected with Maturity Onset Diabetes of The Young 3 (examples: Johansen_2005, Ng_1999, Pruhova_2003, Wang_2019). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.607C>T, p.Arg203Cys), supporting the critical relevance of codon 203 to HNF1A protein function. Localization studies reveal that this variant affect subcellular localization and thereby protein function (Bjrkhaug_2005). The following publications have been ascertained in the context of this evaluation (PMID: 15928245, 10588527, 12627330, 30293189, 16274290). ClinVar contains an entry for this variant (Variation ID: 129235). Based on the evidence outlined above, the variant was classified as pathogenic. -
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. -
Monogenic diabetes Pathogenic:1
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. -
Diabetes mellitus type 1 Pathogenic:1
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). -
Maturity-onset diabetes of the young type 3 Pathogenic:1
PS4, PP1_Strong, PM1, PM2, PP4_Moderate, PP3, PS3_Supporting -
HNF1A-related disorder Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at