rs137853238
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PP3PM2_SupportingPS4PP1_StrongPS3_Supporting
This summary comes from the ClinGen Evidence Repository: 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 HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA124460/MONDO:0015967/017
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.815G>A | p.Arg272His | missense_variant | 4/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.815G>A | p.Arg272His | missense_variant | 4/10 | ||
HNF1A | NM_001406915.1 | c.815G>A | p.Arg272His | missense_variant | 4/9 | ||
HNF1A | XM_024449168.2 | c.815G>A | p.Arg272His | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.815G>A | p.Arg272His | missense_variant | 4/10 | 1 | NM_000545.8 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 14, 2022 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2022 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 29, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 23, 2023 | 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. - |
Maturity onset diabetes mellitus in young Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 09, 2019 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Madras Diabetes Research Foundation | - | - - |
Monogenic diabetes Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Translational Genomics Laboratory, University of Maryland School of Medicine | Jun 04, 2015 | 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 - |
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Jul 05, 2022 | 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. - |
Type 1 diabetes mellitus 20 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1997 | - - |
Maturity-onset diabetes of the young type 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 25, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at