chr12-120994264-C-T
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PP4_ModeratePP3PM2_SupportingPS4PP1_StrongPM5PM1PS3_Supporting
This summary comes from the ClinGen Evidence Repository: The c.814C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to cystine at codon 272 (p.(Arg272Cys) of transcript, e.g. 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.941, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 18003757, 28701371, 25414397, 11719843, 10447526; internal lab contributors). The variant segregated with diabetes, with at least fifteen informative meioses in at least sixteen families with MODY (PP1_Strong; internal lab contributors). Another missense variant, c. 815G>A, p.Arg272His, has been interpreted as pathogenic by the ClinGen MDEP and p.Arg272Cys has a greater Grantham distance (PM5). Functional studies demonstrated the p.Arg272Cys protein has DNA binding below 40% of wild type and transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID:10333057). Lastly, this variant was identified in at least five individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylurea) (PP4_Moderate; internal lab contributors). In summary, c.814C>T, meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PM2_Supporting, PP3, PS4, PP1_Strong, PM5, PS3_Supporting, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386966363/MONDO:0015967/017
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| HNF1A | NM_000545.8 | c.814C>T | p.Arg272Cys | missense_variant | Exon 4 of 10 | ENST00000257555.11 | NP_000536.6 | |
| HNF1A | NM_001306179.2 | c.814C>T | p.Arg272Cys | missense_variant | Exon 4 of 10 | NP_001293108.2 | ||
| HNF1A | NM_001406915.1 | c.814C>T | p.Arg272Cys | missense_variant | Exon 4 of 9 | NP_001393844.1 | ||
| HNF1A | XM_024449168.2 | c.814C>T | p.Arg272Cys | missense_variant | Exon 4 of 9 | XP_024304936.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| HNF1A | ENST00000257555.11 | c.814C>T | p.Arg272Cys | missense_variant | Exon 4 of 10 | 1 | NM_000545.8 | ENSP00000257555.5 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 33
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:4
This variant has been identified in multiple unrelated individuals with clinical features associated with this gene including a de novo case. This variant appears to segregate with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant protein abolished DNA binding and transactivation activity (PMID: 10333057). The variant is located in a region that is considered important for protein function and/or structure. -
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg272 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9032114, 21823540, 29439679). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HNF1A function (PMID: 10333057). 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: 447503). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 10333057, 11719843, 16562587). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 272 of the HNF1A protein (p.Arg272Cys). -
The HNF1A c.814C>T; p.Arg272Cys variant (rs1555212014) is reported in the literature in multiple individuals affected with maturity-onset diabetes of the young (MODY, Kagami-Takasugi 2006, Kristinsson 2001, Yoshiuchi 1999). Functional analyses of the variant protein show abolished transactivation activity and DNA binding (Yoshiuchi 1999). This variant is reported in ClinVar (Variation ID: 447503) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.815G>A, p.Arg272His; c.814C>A, p.Arg272Ser) have been reported in individuals with MODY and are considered pathogenic (Bellanne-Chantelot 2008, Yamada 1997). The arginine at codon 272 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.941). Based on available information, this variant is considered to be pathogenic. References: Bellanne-Chantelot C et al. The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. Diabetes. 2008 Feb;57(2):503-8. PMID: 18003757. Kagami-Takasugi M et al. Molecular genetic analysis of MODY candidate genes in Japanese patients with non-obese juvenile onset diabetes mellitus. J Pediatr Endocrinol Metab. 2006 Feb;19(2):143-8. PMID: 16562587 Kristinsson SY et al. MODY in Iceland is associated with mutations in HNF-1alpha and a novel mutation in NeuroD1. Diabetologia. 2001 Nov;44(11):2098-103. PMID: 11719843 Yamada S et al. Identification of mutations in the hepatocyte nuclear factor (HNF)-1 alpha gene in Japanese subjects with IDDM. Diabetes. 1997 Oct;46(10):1643-7. PMID: 9313763. Yoshiuchi I et al. Three new mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with diabetes mellitus: clinical features and functional characterization. Diabetologia. 1999 May;42(5):621-6. PMID: 10333057 -
Published in vitro functional studies demonstrate a dominant negative effect resulting in no trans-activating or DNA-binding activity (Yoshiuchi 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: 25414397, 10333057, 28701371, 18003757, 16562587, 16274290, 10447526, 11719843, 12453420) -
Maturity onset diabetes mellitus in young Pathogenic:2
The p.R272C pathogenic mutation (also known as c.814C>T), located in coding exon 4 of the HNF1A gene, results from a C to T substitution at nucleotide position 814. The arginine at codon 272 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was first reported in a Japanese patient with a clinical diagnosis of MODY; this mutation was shown to abolish transactivation activity, resulting in impaired insulin and glucagon secretion due to a dominant negative effect (Yoshiuchi I, Diabetologia 1999 May; 42(5):621-6). This mutation has since been reported in multiple MODY patients and kindreds (Lehto M, Diabetologia 1999 Sep; 42(9):1131-7; Kristinsson SY, Diabetologia 2001 Nov; 44(11):2098-103; Delvecchio M, Diabetes Care 2014 Dec; 37(12):e258-60). In addition, alterations at the same codon (p.R272H and p.R272S) have been reported in MODY families (Colclough K, Hum. Mutat. 2013 May; 34(5):669-85). Based on the supporting evidence, p.R272C is interpreted as a disease-causing mutation. -
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. However, more evidence is required to confer the association of this particular variant rs1555212014 with MODY3. -
Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1
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Monogenic diabetes Pathogenic:1
The c.814C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to cystine at codon 272 (p.(Arg272Cys) of transcript, e.g. 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.941, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 18003757, 28701371, 25414397, 11719843, 10447526; internal lab contributors). The variant segregated with diabetes, with at least fifteen informative meioses in at least sixteen families with MODY (PP1_Strong; internal lab contributors). Another missense variant, c. 815G>A, p.Arg272His, has been interpreted as pathogenic by the ClinGen MDEP and p.Arg272Cys has a greater Grantham distance (PM5). Functional studies demonstrated the p.Arg272Cys protein has DNA binding below 40% of wild type and transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 10333057). Lastly, this variant was identified in at least five individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylurea) (PP4_Moderate; internal lab contributors). In summary, c.814C>T, meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PM2_Supporting, PP3, PS4, PP1_Strong, PM5, PS3_Supporting, PP4_Moderate. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at