ClinVar Genomic variation as it relates to human health
NM_000545.8(HNF1A):c.779C>T (p.Thr260Met)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000545.8(HNF1A):c.779C>T (p.Thr260Met)
Variation ID: 265436 Accession: VCV000265436.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 120994229 (GRCh38) [ NCBI UCSC ] 12: 121432032 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 10, 2016 Feb 14, 2024 Apr 13, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000545.8:c.779C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000536.6:p.Thr260Met missense NM_000545.6(HNF1A):c.779C>T NM_001306179.2:c.779C>T NP_001293108.2:p.Thr260Met missense NC_000012.12:g.120994229C>T NC_000012.11:g.121432032C>T NG_011731.2:g.20484C>T LRG_522:g.20484C>T LRG_522t1:c.779C>T - Protein change
- T260M
- Other names
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- Canonical SPDI
- NC_000012.12:120994228:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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HNF1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
875 | 961 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 25, 2023 | RCV000255526.14 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 8, 2023 | RCV001248918.6 | |
Pathogenic (1) |
reviewed by expert panel
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Apr 13, 2022 | RCV002222028.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Apr 13, 2022)
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reviewed by expert panel
Method: curation
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Monogenic diabetes
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Monogenic Diabetes Variant Curation Expert Panel
Accession: SCV002499541.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
The c.779C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 260 (p.(Thr260Met)) of NM_000545.8. … (more)
The c.779C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 260 (p.(Thr260Met)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, 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 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 28 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMIDs: 30760653, 29927023, 30663027, 29207974, 28105082, internal lab contributors). At least two of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A, and both were antibody negative and one responded to low dose sulfonylureas) (PP4_Moderate; PMIDs: 30760653, 281505082). This variant segregated with diabetes, with 16 informative meioses in multiple families with MODY (PP1_Strong; PMIDs: 30760653. 28105082, internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Thr260Met protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate; PMID: 32910913). In summary, c.779C>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_supporting, PM2_Supporting, PP3, PS4, PP4_Moderate, PP1_Strong, PS3_Moderate. (less)
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Pathogenic
(Feb 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000844429.1
First in ClinVar: Oct 10, 2016 Last updated: Oct 10, 2016 |
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Likely pathogenic
(Dec 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002070470.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.779C>T, in exon 4 that results in an amino acid change, p.Thr260Met. This sequence … (more)
DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.779C>T, in exon 4 that results in an amino acid change, p.Thr260Met. This sequence change has been described in gnomAD in one individual in the East Asian subpopulation (dbSNP rs886039544). The p.Thr260Met change affects a highly conserved amino acid residue located in a domain of the HNF1A protein that is known to be functional. The p.Thr260Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in multiple individual with MODY (PMID: 9166684, 23607861, 28105082, 15928245, 18003757, 30455330, 9045858). Experimental studies have demonstrated that this sequence change impacts the function of the HNF1A protein (PMID: 30507613, 23607861, 30455330). (less)
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Likely pathogenic
(Jan 13, 2020)
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criteria provided, single submitter
Method: curation
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Maturity onset diabetes mellitus in young
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422677.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Thr260Met variant in HNF1A has been reported in 13 individual with MODY, segregated with disease in 3 affected relatives from 1 family (PMID: 21224407, … (more)
The p.Thr260Met variant in HNF1A has been reported in 13 individual with MODY, segregated with disease in 3 affected relatives from 1 family (PMID: 21224407, 22060211, 28105082, 28701371, 19754856, 20132997, 9045858, 15928245, 18003757, 23607861), and has been identified in 0.005% (1/18322) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886039544). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that the p.Thr260Met variant may impact protein function (PMID: 30455330, 30507613, 23607861). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Thr260Met is located in a region of HNF1A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 28105082, 12453420). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_moderate, PS4_moderate, PM1, PM2_supporting, PP3, PP1 (Richards 2015). (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
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Maturity onset diabetes mellitus in young
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
unknown
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002605473.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
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. … (more)
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 rs886039544 with MODY3. (less)
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Pathogenic
(Dec 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000322330.8
First in ClinVar: Oct 10, 2016 Last updated: Dec 17, 2022 |
Comment:
Published functional studies demonstrate that T260M significantly inhibits the normal regulatory effects of HNF1A, and causes increased bile acid synthesis (Ekholm et al., 2013); In … (more)
Published functional studies demonstrate that T260M significantly inhibits the normal regulatory effects of HNF1A, and causes increased bile acid synthesis (Ekholm et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22060211, 21224407, 20132997, 18003757, 21170474, 16496320, 30851333, 30663027, 23607861, 9045858, 11058894, 28105082, 9166684, 20393147, 29207974, 28701371, 19754856, 15928245, 12453420, 30760653) (less)
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Pathogenic
(Aug 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004038404.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: HNF1A c.779C>T (p.Thr260Met) results in a non-conservative amino acid change located in the Homeobox domain (IPR001356) of the encoded protein sequence. Five of … (more)
Variant summary: HNF1A c.779C>T (p.Thr260Met) results in a non-conservative amino acid change located in the Homeobox domain (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 4e-06 in 249268 control chromosomes. c.779C>T has been reported in the literature as co-segregating with disease in multiple individuals affected with Maturity Onset Diabetes Of The Young 3 (example, Lehto_1997). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Ekholm_2013). The most pronounced variant effect results in an abolished activation of the cytochrome P450 7A1 (CYP7A1), Farnesoid X receptor (FXR), Small heterodimeric partner (SHP) and Apical sodium-dependent bile salt transporter (ASBT) promoters in-vitro. Six submitters including the ClinGen Monogenic Diabetes Variant Curation Expert Panel have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publications have been ascertained in the context of this evaluation (PMID: 11942313, 9166684, 10333057, 16496320, 12453420, 17924661, 9045858, 23607861). All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002240643.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HNF1A function (PMID: 23607861). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HNF1A function (PMID: 23607861). 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: 265436). This missense change has been observed in individuals with maturity-onset diabetes of the young (PMID: 9166684, 15928245, 23607861, 28105082, 30663027; Invitae). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 260 of the HNF1A protein (p.Thr260Met). (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells. | Low BSJ | Nature communications | 2021 | PMID: 34035238 |
High frequency of pathogenic and rare sequence variants in diabetes-related genes among Russian patients with diabetes in pregnancy. | Zubkova N | Acta diabetologica | 2019 | PMID: 30663027 |
Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks. | Haliyur R | The Journal of clinical investigation | 2019 | PMID: 30507613 |
Plasma Fucosylated Glycans and C-Reactive Protein as Biomarkers of HNF1A-MODY in Young Adult-Onset Nonautoimmune Diabetes. | Juszczak A | Diabetes care | 2019 | PMID: 30455330 |
Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals. | Bansal V | BMC medicine | 2017 | PMID: 29207974 |
Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients. | Shields BM | Diabetes care | 2017 | PMID: 28701371 |
Genetic diagnosis and treatment of a Chinese ketosis-prone MODY 3 family with depression. | Tang J | Diabetology & metabolic syndrome | 2017 | PMID: 28105082 |
Half-Life of Sulfonylureas in HNF1A and HNF4A Human MODY Patients is not Prolonged as Suggested by the Mouse Hnf1a(-/-) Model. | Urbanova J | Current pharmaceutical design | 2015 | PMID: 26446475 |
Alterations in bile acid synthesis in carriers of hepatocyte nuclear factor 1α mutations. | Ekholm E | Journal of internal medicine | 2013 | PMID: 23607861 |
Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus. | Yorifuji T | Pediatric diabetes | 2012 | PMID: 22060211 |
Genetic and clinical characteristics of patients with HNF1A gene variations from the German-Austrian DPV database. | Awa WL | European journal of endocrinology | 2011 | PMID: 21224407 |
Spectrum of HNF1A somatic mutations in hepatocellular adenoma differs from that in patients with MODY3 and suggests genotoxic damage. | Jeannot E | Diabetes | 2010 | PMID: 20393147 |
Three novel mutations in MODY and its phenotype in three different Czech families. | Bazalová Z | Diabetes research and clinical practice | 2010 | PMID: 20132997 |
An investigation of serum concentration of apoM as a potential MODY3 marker using a novel ELISA. | Cervin C | Journal of internal medicine | 2010 | PMID: 19754856 |
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. | Bellanné-Chantelot C | Diabetes | 2008 | PMID: 18003757 |
Structural basis of disease-causing mutations in hepatocyte nuclear factor 1beta. | Lu P | Biochemistry | 2007 | PMID: 17924661 |
Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. | Zucman-Rossi J | Hepatology (Baltimore, Md.) | 2006 | PMID: 16496320 |
Half of clinically defined maturity-onset diabetes of the young patients in Denmark do not have mutations in HNF4A, GCK, and TCF1. | Johansen A | The Journal of clinical endocrinology and metabolism | 2005 | PMID: 15928245 |
Diabetes mutations delineate an atypical POU domain in HNF-1alpha. | Chi YI | Molecular cell | 2002 | PMID: 12453420 |
To: Lindner T, Cockburn BN, Bell GI (1999). Molecular genetics of MODY in Germany. Diabetologia 42: 121-123. | Ziemssen F | Diabetologia | 2002 | PMID: 11942313 |
Three new mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with diabetes mellitus: clinical features and functional characterization. | Yoshiuchi I | Diabetologia | 1999 | PMID: 10333057 |
Novel mutations and a mutational hotspot in the MODY3 gene. | Glucksmann MA | Diabetes | 1997 | PMID: 9166684 |
Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect. | Lehto M | The Journal of clinical investigation | 1997 | PMID: 9045858 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/9a769788-7d73-494d-8ca2-f64268763e26 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b5943d8b-4ba3-402c-879f-9049fe2f8a98 | - | - | - | - |
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Text-mined citations for rs886039544 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.