ClinVar Genomic variation as it relates to human health
NM_000545.8(HNF1A):c.685C>T (p.Arg229Ter)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000545.8(HNF1A):c.685C>T (p.Arg229Ter)
Variation ID: 420064 Accession: VCV000420064.42
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 120993678 (GRCh38) [ NCBI UCSC ] 12: 121431481 (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 Apr 27, 2017 Oct 20, 2024 Dec 30, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000545.8:c.685C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000536.6:p.Arg229Ter nonsense NM_001306179.2:c.685C>T NP_001293108.2:p.Arg229Ter nonsense NC_000012.12:g.120993678C>T NC_000012.11:g.121431481C>T NG_011731.2:g.19933C>T LRG_522:g.19933C>T LRG_522t1:c.685C>T - Protein change
- R229*
- Other names
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NM_000545.6(HNF1A):c.685C>T
p.Arg229Ter
- Canonical SPDI
- NC_000012.12:120993677: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.
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- Links
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 |
911 | 1002 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Jul 19, 2024 | RCV000483162.31 | |
Pathogenic (1) |
reviewed by expert panel
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Dec 30, 2021 | RCV001810449.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 2, 2022 | RCV002285337.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2022 | RCV002506168.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 8, 2023 | RCV003298551.4 |
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
(Dec 30, 2021)
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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
FDA Recognized Database
Accession: SCV002059974.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The c.685C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 229 (p.(Arg229Ter)) of NM_000545.8. This variant, located in … (more)
The c.685C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 229 (p.(Arg229Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in at least 34 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 29666556, 23517481, 25411618, internal lab contributors). This variant segregated with diabetes, with at least 13 informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). In summary, c.685C>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 6/4/2021): PVS1, PM2_Supporting, PS4, PP1_Strong (less)
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Pathogenic
(Aug 02, 2022)
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criteria provided, single submitter
Method: research
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Maturity-onset diabetes of the young type 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Geisinger Clinic, Geisinger Health System
Accession: SCV002562143.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
PVS1, PM2, PS4, PP1_Strong, PP4
Number of individuals with the variant: 1
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Pathogenic
(Mar 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Type 2 diabetes mellitus
Hepatic adenomas, familial Nonpapillary renal cell carcinoma Diabetes mellitus type 1 Maturity-onset diabetes of the young type 3 Type 1 diabetes mellitus 20
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002808699.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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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: SCV004038405.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: HNF1A c.685C>T (p.Arg229X) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which … (more)
Variant summary: HNF1A c.685C>T (p.Arg229X) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 8e-06 in 251144 control chromosomes. c.685C>T has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 3 (example, Furuzawa_2008). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9032114, 10078571, 10333057, 16602010, 14598263, 12355088, 17407387, 18672310). Eight submitters including the ClinGen Monogenic Diabetes Variant Curation Expert Panel have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV004229331.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more)
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families. (less)
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Pathogenic
(Sep 30, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002243185.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg229*) in the HNF1A gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg229*) in the HNF1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1A are known to be pathogenic (PMID: 15928245, 18003757). This variant is present in population databases (rs769086289, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 9032114, 29666556). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 420064). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 05, 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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Ambry Genetics
Accession: SCV004007060.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The p.R229* pathogenic mutation (also known as c.685C>T), located in coding exon 3 of the HNF1A gene, results from a C to T substitution at … (more)
The p.R229* pathogenic mutation (also known as c.685C>T), located in coding exon 3 of the HNF1A gene, results from a C to T substitution at nucleotide position 685. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been reported in several individuals and families with maturity-onset diabetes of the young (Kaisaki PJ et al. Diabetes, 1997 Mar;46:528-35; Ohki T et al. J Diabetes Investig, 2014 Sep;5:513-6; Goodrich JK et al. Nat Commun, 2021 Jun;12:3505; Mirshahi UL et al. Am J Hum Genet, 2022 Nov;109:2018-2028). Other families have presented with no evidence of glucose dysfunction, but with only hepatocellular adenomas (Barbier L et al. J Hepatol, 2019 Dec;71:1184-1192; Bacq Y et al. Gastroenterology, 2003 Nov;125:1470-5). In one family, the proband presented with diabetes and the mother had multiple liver adenomas without diabetes (Globa E et al. J Pediatr Endocrinol Metab, 2017 Oct;30:1095-1103). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 19, 2024)
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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: SCV000568551.5
First in ClinVar: Apr 27, 2017 Last updated: Sep 16, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 25411618, 36257325, 9032114, 28862987, 29666556, 29182332, 28012402, 34161864, 30455330, 34789499, 14598263, 34108472, 36208030, 36504295) (less)
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Pathogenic
(Feb 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002497640.18
First in ClinVar: Apr 08, 2022 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 29, 2022)
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no assertion criteria provided
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: SCV003839581.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.685C>T, which results in the creation of a premature stop codon at amino acid … (more)
DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.685C>T, which results in the creation of a premature stop codon at amino acid position 229, . p.Arg229*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated HNF1A protein with potentially abnormal function. This sequence change has been described in the gnomAD database in two individuals which corresponds to a population frequency of 0.00080% (dbSNP rs769086289). This sequence change has previously been described in multiple individuals with HNF1A-related diabetes (PMID: 29666556, 23517481, 25411618, 28862987, 9032114). Based on these evidences, this sequence change is classified as pathogenic. (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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Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. | Mirshahi UL | American journal of human genetics | 2022 | PMID: 36257325 |
Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort. | Billings LK | Endocrinology, diabetes & metabolism | 2022 | PMID: 36208030 |
The Clinical Characteristics and Gene Mutations of Maturity-Onset Diabetes of the Young Type 5 in Sixty-One Patients. | Ge S | Frontiers in endocrinology | 2022 | PMID: 35846334 |
A case of digenic maturity onset diabetes of the young with heterozygous variants in both HNF1Α and HNF1Β genes. | Patouni K | European journal of medical genetics | 2021 | PMID: 34161864 |
Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. | Goodrich JK | Nature communications | 2021 | PMID: 34108472 |
Natural history of liver adenomatosis: A long-term observational study. | Barbier L | Journal of hepatology | 2019 | PMID: 31419515 |
Maturity onset diabetes of the young due to HNF1A variants in Croatia. | Pavić T | Biochemia medica | 2018 | PMID: 29666556 |
MODY in Ukraine: genes, clinical phenotypes and treatment. | Globa E | Journal of pediatric endocrinology & metabolism : JPEM | 2017 | PMID: 28862987 |
Low serum level of high-sensitivity C-reactive protein in a Japanese patient with maturity-onset diabetes of the young type 3 (MODY3). | Ohki T | Journal of diabetes investigation | 2014 | PMID: 25411618 |
Low prevalence of MODY2 and MODY3 mutations in Brazilian individuals with clinical MODY phenotype. | Furuzawa GK | Diabetes research and clinical practice | 2008 | PMID: 18672310 |
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 |
Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. | Pearson ER | PLoS medicine | 2007 | PMID: 17407387 |
Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents. | Feigerlová E | European journal of pediatrics | 2006 | PMID: 16602010 |
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 |
Familial liver adenomatosis associated with hepatocyte nuclear factor 1alpha inactivation. | Bacq Y | Gastroenterology | 2003 | PMID: 14598263 |
Bi-allelic inactivation of TCF1 in hepatic adenomas. | Bluteau O | Nature genetics | 2002 | PMID: 12355088 |
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 |
Identification of mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with early-onset NIDDM and functional analysis of the mutant proteins. | Yamada S | Diabetes | 1999 | PMID: 10078571 |
Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4. | Kaisaki PJ | Diabetes | 1997 | PMID: 9032114 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ef883e91-9835-45c6-8c64-acb061f549b0 | - | - | - | - |
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Text-mined citations for rs769086289 ...
HelpRecord last updated Nov 03, 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.