ClinVar Genomic variation as it relates to human health
NM_000545.8(HNF1A):c.511C>T (p.Arg171Ter)
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.511C>T (p.Arg171Ter)
Variation ID: 377965 Accession: VCV000377965.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 120989017 (GRCh38) [ NCBI UCSC ] 12: 121426820 (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 Mar 8, 2017 Feb 14, 2024 Apr 10, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000545.8:c.511C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000536.6:p.Arg171Ter nonsense NM_001306179.2:c.511C>T NP_001293108.2:p.Arg171Ter nonsense NC_000012.12:g.120989017C>T NC_000012.11:g.121426820C>T NG_011731.2:g.15272C>T LRG_522:g.15272C>T LRG_522t1:c.511C>T - Protein change
- R171*
- Other names
- NM_000545.8(HNF1A):c.511C>T
- p.Arg171Ter
- Canonical SPDI
- NC_000012.12:120989016: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
Help
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
Help
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 (3) |
criteria provided, multiple submitters, no conflicts
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Jul 24, 2023 | RCV000436030.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 21, 2017 | RCV002338986.1 | |
Pathogenic (1) |
reviewed by expert panel
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Apr 10, 2022 | RCV002222032.3 |
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
Help
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 10, 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: SCV002499509.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
The c.511C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 171 (p.(Arg171Ter)) of NM_000545.8. This variant, located in … (more)
The c.511C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 171 (p.(Arg171Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 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). This variant segregated with diabetes, with 13 informative meioses in 5 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in 14 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 9097962, 10102714, 12530534, 12574234, internal lab contributors). 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 negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.511C>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 September 30, 2021): PVS1, PS4, PP1_Strong, PM2_Supporting, PP4_Moderate. (less)
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Pathogenic
(Feb 21, 2017)
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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: SCV002642221.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R171* pathogenic mutation (also known as c.511C>T), located in coding exon 2 of the HNF1A gene, results from a C to T substitution at … (more)
The p.R171* pathogenic mutation (also known as c.511C>T), located in coding exon 2 of the HNF1A gene, results from a C to T substitution at nucleotide position 511. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been observed to co-segregate with disease in families with maturity-onset diabetes of the young (MODY) (Vaxillaire M et al, Hum. Mol. Genet. 1997; 6(4):583-6; Bjørkhaug et al, J. Clin. Endocrinol. Metab. 2003; 88(2):920-31) and has been reported in multiple proband's with a MODY phenotype (Bennett JT et al. Mol. Genet. Metab., 2015 Mar;114:451-8; de Santana LS et al. Clin. Genet., 2017 Feb; [Epub ahead of print]). Functional studies demonstrated that this mutation significantly decreases transcriptional activity and results in the absence of DNA binding ability (Bjørkhaug et al, J. Clin. Endocrinol. Metab. 2003; 88(2):920-31). 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)
Number of individuals with the variant: 1
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Pathogenic
(Dec 06, 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: SCV000513245.5
First in ClinVar: Mar 08, 2017 Last updated: Dec 17, 2022 |
Comment:
Published functional studies demonstrate reduced DNA binding ability, transactivation potential and impaired mRNA stability (Thomas et al., 2002); Nonsense variant predicted to result in protein … (more)
Published functional studies demonstrate reduced DNA binding ability, transactivation potential and impaired mRNA stability (Thomas et al., 2002); 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29439679, 9097962, 12574234, 27420379, 26641800, 12530534) (less)
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Pathogenic
(Nov 15, 2021)
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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 Inc
Accession: SCV000613619.2
First in ClinVar: Mar 08, 2017 Last updated: Dec 31, 2022 |
Comment:
This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). … (more)
This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show that this variant results in reduced transactivation activity as well as loss of DNA binding activity (PMID: 10585442, 12107757, 12530534, 12574234). The variant is located in a region that is considered important for protein function and/or structure. (less)
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Pathogenic
(Jul 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: SCV002241489.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 377965). This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young 3 (PMID: 9097962). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg171*) 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). (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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A Comprehensive Analysis of Hungarian MODY Patients-Part I: Gene Panel Sequencing Reveals Pathogenic Mutations in HNF1A, HNF1B, HNF4A, ABCC8 and INS Genes. | Gaál Z | Life (Basel, Switzerland) | 2021 | PMID: 34440499 |
MODY probability calculator for GCK and HNF1A screening in a multiethnic background population. | Tarantino RM | Archives of endocrinology and metabolism | 2020 | PMID: 31576961 |
Somatic HNF1A mutations in the malignant transformation of hepatocellular adenomas: a retrospective analysis of data from MSK-IMPACT and TCGA. | Hechtman JF | Human pathology | 2019 | PMID: 30121369 |
Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India. | Mohan V | BMC medical genetics | 2018 | PMID: 29439679 |
Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families. | Santana LS | Clinical genetics | 2017 | PMID: 28170077 |
Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism. | Bennett JT | Molecular genetics and metabolism | 2015 | PMID: 25555642 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
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 |
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 |
Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients. | Xu JY | European journal of human genetics : EJHG | 2005 | PMID: 15657605 |
Hepatocyte nuclear factor-1 alpha gene mutations and diabetes in Norway. | Bjørkhaug L | The Journal of clinical endocrinology and metabolism | 2003 | PMID: 12574234 |
Evidence for haploinsufficiency of the human HNF1alpha gene revealed by functional characterization of MODY3-associated mutations. | Thomas H | Biological chemistry | 2002 | PMID: 12530534 |
Mutations in the hepatocyte nuclear factor-1alpha gene in Chinese MODY families: prevalence and functional analysis. | Xu JY | Diabetologia | 2002 | PMID: 12107757 |
Anatomy of a homeoprotein revealed by the analysis of human MODY3 mutations. | Vaxillaire M | The Journal of biological chemistry | 1999 | PMID: 10585442 |
Allelic drop-out in exon 2 of the hepatocyte nuclear factor-1alpha gene hinders the identification of mutations in three families with maturity-onset diabetes of the young. | Ellard S | Diabetes | 1999 | PMID: 10102714 |
Hepatocyte nuclear factor 1alpha coding mutations are an uncommon contributor to early-onset type 2 diabetes in Ashkenazi Jews. | Behn PS | Diabetes | 1998 | PMID: 9604876 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b56e5c2d-f615-46c2-9373-143f326142cb | - | - | - | - |
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Text-mined citations for rs1057520291 ...
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.