Submissions for variant NM_000545.8(HNF1A):c.815G>A (p.Arg272His)

dbSNP: rs137853238

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV000445525	SCV002558824	pathogenic	Monogenic diabetes	2022-07-05	reviewed by expert panel	curation	The c.815G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 272 (p.(Arg272His)) of NM_000545.8. This variant resides in an amino acid within the HNF1alpha DNA binding domain that directly binds DNA, which is defined as critical for the protein function by the ClinGen MDEP (PM1). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.961, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified in at least 18 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:31166087, PMID:18003757, PMID:24905847, PMID:31483937, PMID:29439679, PMID:23610083, PMID:21989397, PMID:21395678, PMID:21224407, PMID:15114102, ClinVar ID 14931, internal lab contributors). This variant segregated with diabetes, with 13 informative meioses in multiple families with MODY (PP1_Strong; PMID:15114102, internal lab contributors). Functional studies demonstrated the p.Arg272His protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 16781669). In summary, c.815G>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 9/30/2021): PP1_Strong, PS4, PM1, PP3, PM2_Supporting, PS3_Supporting.
GeneDx	RCV000255916	SCV000322331	pathogenic	not provided	2022-02-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate normal expression level and mobility, but reduced DNA binding and decreased transactivation activity compared to wild-type (Vaxillaire et al., 1999); 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: 9313763, 27077911, 21823540, 28410371, 15114102, 31483937, 9166684, 9032114, 26431509, 29439679, 29207974, 31960584, 33242514, 23610083, 12453420, 18003757, 19150152, 10333057, 11719843, 10585442)
Translational Genomics Laboratory, University of Maryland School of Medicine	RCV000445525	SCV000537127	pathogenic	Monogenic diabetes	2015-06-04	criteria provided, single submitter	clinical testing	The c.815G>A (p.(Arg272His)) pathogenic variant in the HNF1A gene has been reported previously in patients with Maturity-Onset Diabetes of the Young, Type 3 (MODY3) (9313763, 11463573, 19150152, 9032114). The variant tracks with disease incidence across multiple generations in multiple families (9032114, AACE report). The c.815G>A variant was not observed in the NHLBI Exome Sequencing Project (ESP), 1000 Genomes Project, or Exome Aggregation Consortium (ExAC) databases. Multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, LRT, CADD, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. In particular, the c.815G>A variant is located within helix 3 of the homeodomain DNA binding motif, a part of the domain strictly conserved among all known homeodomain sequences (10585442, 15726414). Electrophoretic mobility shift assays showed the p.Arg272His variant has reduced DNA binding activity compared to the normal protein (10585442); ACMG Criteria = PS3, PM1, PM2, PP3, PP5, PP1
Athena Diagnostics	RCV000255916	SCV000844431	pathogenic	not provided	2023-08-23	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with MODY and segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10585442, 37396188) The variant is located in a region that is considered important for protein function and/or structure.
Genetic Services Laboratory, University of Chicago	RCV000255916	SCV002072230	pathogenic	not provided	2021-03-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255916	SCV002224971	pathogenic	not provided	2022-07-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt HNF1A protein function. ClinVar contains an entry for this variant (Variation ID: 14931). This missense change has been observed in individuals with maturity-onset diabetes of the young (MODY) (PMID: 9032114, 21823540, 29439679). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 272 of the HNF1A protein (p.Arg272His).
Molecular Genetics, Madras Diabetes Research Foundation	RCV002051786	SCV002318440	likely pathogenic	Maturity onset diabetes mellitus in young		criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288493	SCV002580072	pathogenic	Maturity-onset diabetes of the young type 3	2022-08-25	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002051786	SCV002605469	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 rs137853238 with MODY3.
Ambry Genetics	RCV002051786	SCV002680355	pathogenic	Maturity onset diabetes mellitus in young	2019-03-09	criteria provided, single submitter	clinical testing	The p.R272H pathogenic mutation (also known as c.815G>A), located in coding exon 4 of the HNF1A gene, results from a G to A substitution at nucleotide position 815. The arginine at codon 272 is replaced by histidine, an amino acid with highly similar properties. This variant has been described in multiple patients and families with a MODY diagnosis (Klupa T et al. Diabetes Care, 2002 Dec;25:2292-301; Pruhova S et al. Diabetologia, 2003 Feb;46:291-5; McDonald TJ et al. Diabet. Med., 2011 Sep;28:1028-33) and has segregated with disease in multiple families (Rozenkova K et al. J. Clin. Endocrinol. Metab., 2015 Dec;100:E1540-9; Dusátková P et al. J. Pediatr. Endocrinol. Metab., 2011;24:377-9; Glucksmann MA et al. Diabetes, 1997 Jun;46:1081-6). One report included an individual heterozygous for this alteration who developed diabetic ketoacidosis due to poor control and dehydration. (Pruhova S et al. Diabetes Care, 2013 Sep;36:2573-4). In addition, alterations at the same codon (p.R272C and p.R272S) have been reported in MODY families (Colclough K, Hum. Mutat. 2013 May; 34(5):669-85). Based on internal structural analysis, this variant may modestly disrupt an important non-specific protein-DNA interaction (Chi YI et al. Mol. Cell, 2002 Nov;10:1129-37). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000016068	SCV000036336	pathogenic	Type 1 diabetes mellitus 20	1997-10-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004752708	SCV005360021	pathogenic	HNF1A-related disorder	2024-07-02	no assertion criteria provided	clinical testing	The HNF1A c.815G>A variant is predicted to result in the amino acid substitution p.Arg272His. This variant was reported to be pathogenic for autosomal dominant maturity onset diabetes of the young (MODY) in multiple affected patients (Kaisaki et al. 1997. PubMed ID: 9032114; Pruhova et al. 2013. PubMed ID: 23610083; Mohan et al. 2018. PubMed ID: 29439679; Passanisi et al. 2021. PubMed ID: 34496959). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.