ClinVar Genomic variation as it relates to human health
NM_000545.8(HNF1A):c.475C>T (p.Arg159Trp)
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.475C>T (p.Arg159Trp)
Variation ID: 429750 Accession: VCV000429750.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 120988981 (GRCh38) [ NCBI UCSC ] 12: 121426784 (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 Jul 2, 2017 Feb 14, 2024 Dec 22, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000545.8:c.475C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000536.6:p.Arg159Trp missense NM_001306179.2:c.475C>T NP_001293108.2:p.Arg159Trp missense NC_000012.12:g.120988981C>T NC_000012.11:g.121426784C>T NG_011731.2:g.15236C>T LRG_522:g.15236C>T LRG_522t1:c.475C>T - Protein change
- R159W
- Other names
- NM_000545.6(HNF1A):c.475C>T
- p.Arg159Trp
- Canonical SPDI
- NC_000012.12:120988980: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
Trans-Omics for Precision Medicine (TOPMed) 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 |
872 | 958 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2023 | RCV000494442.13 | |
Likely pathogenic (1) |
no assertion criteria provided
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Apr 28, 2020 | RCV001175312.9 | |
Pathogenic (1) |
reviewed by expert panel
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Dec 22, 2021 | RCV001810450.10 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 2, 2022 | RCV002272261.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2023 | RCV002464213.11 |
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
Help
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 22, 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
Accession: SCV002059982.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The c.475C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 159 (p.(Arg159Trp)) of NM_000545.8. … (more)
The c.475C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 159 (p.(Arg159Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.907, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified in multiple individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.476G>A, p.(Arg159Gln), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg159Trp has an equal or greater Grantham distance. (PM5). This variant was identified in thirteen unrelated families with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; [internal lab contributors; Exeter, BMRC, Paris]). Lastly, this variant segregated with diabetes, with eight informative meioses in five families with MODY (PP1_Strong; [internal lab contributors; Exeter]). In summary, c.475C>T meets the criteria to be classified as pathogneic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 6/4/2021): PP3, PP4, PM1_Supporting, PM2_Supporting, PM5, 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: SCV002562135.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
PP3, PP4, PM1_Supporting, PM2, PM5, PS4, PP1_Strong
Number of individuals with the variant: 1
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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: SCV002605468.1
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 rs765432081 with MODY3. (less)
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Likely pathogenic
(Jul 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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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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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556597.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Jan 19, 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: SCV003800817.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Variant summary: HNF1A c.475C>T (p.Arg159Trp) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, N-terminal domain (IPR006899) of the encoded … (more)
Variant summary: HNF1A c.475C>T (p.Arg159Trp) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, N-terminal domain (IPR006899) 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 251546 control chromosomes. c.475C>T has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young (example, PMID: 12050210, 9754819, 9075818, 9313764, 10333057, 18672310, 17937063, 19150152). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories and the ClinGen Monogenic Diabetes Variant Curation Expert Panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. 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
(Feb 28, 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: SCV000582396.5
First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9754819, 12453420, 28410371, 28012402, 11058894, 30191644, 31264968, 33538814, 18003757, 34440499, 34556497, 9075818, 9097962, 23548576) (less)
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Pathogenic
(Jan 24, 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: SCV003442075.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg159 amino acid residue in HNF1A. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg159 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9097962). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 429750). This missense change has been observed in individuals with diabetes (PMID: 9075818, 9754819, 12050210, 18672310, 27083284, 30191644). 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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 159 of the HNF1A protein (p.Arg159Trp). (less)
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Likely pathogenic
(Apr 28, 2020)
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no assertion criteria provided
Method: research
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Diabetes mellitus
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre
Study: T1DGC
Accession: SCV001250628.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
PS1 PM2 PP3
Comment on evidence:
Affected sibling carries the same variant and have diabetes mellitus.
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Likely pathogenic
(Jul 21, 2023)
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no assertion criteria provided
Method: research
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Maturity-onset diabetes of the young type 3
Affected status: yes
Allele origin:
germline
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deCODE genetics, Amgen
Accession: SCV004022263.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_000545.8:c.475C>T (chr12:120988981) in HNF1A was detected in 6 heterozygotes out of 58K WGS Icelanders (MAF= 0,005%). Following imputation in a set of 166K … (more)
The variant NM_000545.8:c.475C>T (chr12:120988981) in HNF1A was detected in 6 heterozygotes out of 58K WGS Icelanders (MAF= 0,005%). Following imputation in a set of 166K Icelanders (12 imputed heterozygotes) we observed an association with diabetes mellitus using 3676 cases and 332804 controls (OR= 14.65, P= 5.32e-03) and non-insulin dependent diabetes mellitus using 5864 cases and 298172 controls (OR= 10.82, P= 1.59e-02). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PS4, PP3, PP5) this variant classifies as likely pathogenic. (less)
Number of individuals with the variant: 12
Ethnicity/Population group: Icelandic
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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 |
Monogenic Causes in the Type 1 Diabetes Genetics Consortium Cohort: Low Genetic Risk for Autoimmunity in Case Selection. | Marchand L | The Journal of clinical endocrinology and metabolism | 2021 | PMID: 33538814 |
Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations. | Alvelos MI | Journal of clinical medicine | 2020 | PMID: 31968686 |
Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort. | Johnson SR | Pediatric diabetes | 2019 | PMID: 30191644 |
Determining the role of missense mutations in the POU domain of HNF1A that reduce the DNA-binding affinity: A computational approach. | P S | PloS one | 2017 | PMID: 28410371 |
Tubular proteinuria in patients with HNF1α mutations: HNF1α drives endocytosis in the proximal tubule. | Terryn S | Kidney international | 2016 | PMID: 27083284 |
Novel mutations in GCK and HNF1A genes in Italian families with MODY phenotype. | Cappelli A | Diabetes research and clinical practice | 2009 | PMID: 19150152 |
Low prevalence of MODY2 and MODY3 mutations in Brazilian individuals with clinical MODY phenotype. | Furuzawa GK | Diabetes research and clinical practice | 2008 | PMID: 18672310 |
Four novel mutations, including the first gross deletion in TCF1, identified in HNF-4alpha, GCK and TCF1 in patients with MODY in Israel. | Stern E | Journal of pediatric endocrinology & metabolism : JPEM | 2007 | PMID: 17937063 |
Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. | Barrio R | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 12050210 |
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 |
Mutation screening in 18 Caucasian families suggest the existence of other MODY genes. | Chèvre JC | Diabetologia | 1998 | PMID: 9754819 |
Maturity-onset diabetes of the young due to a mutation in the hepatocyte nuclear factor-4 alpha binding site in the promoter of the hepatocyte nuclear factor-1 alpha gene. | Gragnoli C | Diabetes | 1997 | PMID: 9313764 |
Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3). | Vaxillaire M | Human molecular genetics | 1997 | PMID: 9097962 |
Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of maturity-onset diabetes of the young in the U.K. | Frayling TM | Diabetes | 1997 | PMID: 9075818 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cb08fbb4-f6a7-453e-8d69-a7c412e82e90 | - | - | - | - |
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Text-mined citations for rs765432081 ...
HelpRecord last updated Feb 20, 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.