rs1057520504
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PP3PM2_SupportingPS4PP1_StrongPS3_SupportingPP4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.788G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 263 (p.Arg263His) 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). This variant 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 0.957, which is greater thanthe MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 16 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 19336507, 26853433, 28012402, 29927023, 31166087, internal lab contributors). Additionally, functional studies demonstrated the p.Arg263His protein has DNA binding and nuclear localization below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID:26853433). 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 response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). Finally, this variant segregated with diabetes, with 9 informative meioses in multiple families with MODY (PP1_Strong; 19336507, internal lab contributors). While two additional missense variants, c.787C>T (p.Arg263His) and c.788G>T (p.Arg263Leu) have been classified as pathogenic by the ClinGen MDEP, p.Arg263His has the lowest Grantham distance and was used as the base variant to apply PM5 to Arg263Cys and PM5_Strong to Arg263Leu and thus PM5 is not applied to p.Arg263His. In summary, c.788G>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): PM1, PM2_Supporting, PP3, PS4, PS3_Supporting, PP4_Moderate, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16606475/MONDO:0015967/017
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.788G>A | p.Arg263His | missense_variant | 4/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.788G>A | p.Arg263His | missense_variant | 4/10 | ||
HNF1A | NM_001406915.1 | c.788G>A | p.Arg263His | missense_variant | 4/9 | ||
HNF1A | XM_024449168.2 | c.788G>A | p.Arg263His | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.788G>A | p.Arg263His | missense_variant | 4/10 | 1 | NM_000545.8 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461296Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726908
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 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) 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. ClinVar contains an entry for this variant (Variation ID: 379138). This missense change has been observed in individuals with maturity-onset diabetes of the young (PMID: 16917892, 19336507, 28395978, 30293189). 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 263 of the HNF1A protein (p.Arg263His). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 13, 2022 | Published functional studies demonstrate reduced transcriptional activity, reduced binding to a HNF1A binding-site, and decreased nuclear and increased cytoplasmic localization of HNF1A compared to wildtype (Balamurugan et al., 2016); 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: 26817999, 20393147, 25525159, 26853433, 16496320, 16917892, 29927023, 23517481, 30293189, 22060211, 28012402, 18838325, 19336507, 28395978, 31166087, 12453420, 18003757) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 14, 2020 | This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant caused reduction in protein transactivation, DNA binding, and nuclear localization when expressed in HeLa cells (PMID 26853433). The variant is located in a region that is considered important for protein function and/or structure. - |
Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Maturity onset diabetes mellitus in young Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2021 | The p.R263H pathogenic mutation (also known as c.788G>A), located in coding exon 4 of the HNF1A gene, results from a G to A substitution at nucleotide position 788. The arginine at codon 263 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in several unrelated individuals reported to have maturity-onset diabetes of the young (MODY) and has shown segregation with disease in a family (Skupien J et al. Diabetes Metab, 2008 Nov;34:524-8; Radha V et al. J Clin Endocrinol Metab. 2009 Jun;94(6):1959-65; Giuffrida FMA et al. Diabetes Res Clin Pract, 2017 Jan;123:134-142; Karaca E et al. Diabetes Metab Syndr, 2017 Nov;11 Suppl 1:S491-S496; Yorifuji T et al. Pediatr Diabetes, 2018 11;19:1164-1172). In in vitro assays, this variant has been suggested to result in reduced function (Balamurugan K et al. Clin Genet. 2016 12;90(6):486-495). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Madras Diabetes Research Foundation | - | - - |
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Apr 14, 2022 | The c.788G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 263 (p.Arg263His) 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). This variant 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 0.957, which is greater thanthe MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 16 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 19336507, 26853433, 28012402, 29927023, 31166087, internal lab contributors). Additionally, functional studies demonstrated the p.Arg263His protein has DNA binding and nuclear localization below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 26853433). 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 response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). Finally, this variant segregated with diabetes, with 9 informative meioses in multiple families with MODY (PP1_Strong; 19336507, internal lab contributors). While two additional missense variants, c.787C>T (p.Arg263His) and c.788G>T (p.Arg263Leu) have been classified as pathogenic by the ClinGen MDEP, p.Arg263His has the lowest Grantham distance and was used as the base variant to apply PM5 to Arg263Cys and PM5_Strong to Arg263Leu and thus PM5 is not applied to p.Arg263His. In summary, c.788G>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): PM1, PM2_Supporting, PP3, PS4, PS3_Supporting, PP4_Moderate, PP1_Strong. - |
Maturity-onset diabetes of the young type 3 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Genomics And Bioinformatics Analysis Resource, Columbia University | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at