ClinVar Genomic variation as it relates to human health
NM_000545.8(HNF1A):c.335C>T (p.Pro112Leu)
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.335C>T (p.Pro112Leu)
Variation ID: 14942 Accession: VCV000014942.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 120988841 (GRCh38) [ NCBI UCSC ] 12: 121426644 (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 Aug 22, 2016 Feb 14, 2024 Apr 8, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000545.8:c.335C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000536.6:p.Pro112Leu missense NM_001306179.2:c.335C>T NP_001293108.2:p.Pro112Leu missense NC_000012.12:g.120988841C>T NC_000012.11:g.121426644C>T NG_011731.2:g.15096C>T LRG_522:g.15096C>T LRG_522t1:c.335C>T - Protein change
- P112L
- Other names
- NM_000545.8(HNF1A):c.335C>T
- p.Pro112Leu
- Canonical SPDI
- NC_000012.12:120988840: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
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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Nov 13, 2023 | RCV000517471.7 | |
Pathogenic (1) |
reviewed by expert panel
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Apr 8, 2022 | RCV002221999.3 | |
Pathogenic (2) |
criteria provided, single submitter
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May 6, 2021 | RCV000016080.28 |
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 08, 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: SCV002499500.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
The c.335C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 112 (p.(Pro112Leu)) of NM_000545.8. … (more)
The c.335C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 112 (p.(Pro112Leu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.966, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, 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). This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant was identified in two 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 sulfonylureas) (PP4_Moderate; internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Pro112Leu protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate, PMID: 32910913). Lastly, this variant segregated with diabetes, with 11 informative meioses in six families with MODY (PP1_Strong; internal lab contributors). In summary, c.335C>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 9/30/21): PP3, PM1_Supporting, PM2_Supporting, PP4_Moderate, PS4_Moderate,PS3_Moderate, PP1_Strong. (less)
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Pathogenic
(Nov 13, 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: SCV004295423.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 112 of the HNF1A protein (p.Pro112Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 112 of the HNF1A protein (p.Pro112Leu). This variant is present in population databases (rs137853243, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of maturity-onset diabetes of the young (MODY) (PMID: 11162430, 21518407). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14942). 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) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects HNF1A function (PMID: 11162430, 27899486, 35472491). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 07, 2016)
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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: SCV000613611.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(May 06, 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: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767355.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with type III maturity-onset diabetes of the young (MODY type III; MIM#600496). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated DNA-binding domain (PMID: 32910913). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple families with MODY (ClinVar, PMIDs: 11162430, 12107757, 21518407, 32238361). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Studies performed by multiple laboratories have shown that it reduced protein expression, transcriptional activity, DNA binding and also resulted in impaired subcellular localisation (PMID: 32910913). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jan 04, 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: SCV002513014.2
First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate impaired DNA binding and significantly reduced transcriptional activity (Bjrkhaug et al., 2000; Xu et al., 2002; Najmi et al., 2016); Not … (more)
Published functional studies demonstrate impaired DNA binding and significantly reduced transcriptional activity (Bjrkhaug et al., 2000; Xu et al., 2002; Najmi et al., 2016); 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: 17989309, 12107757, 12574234, 15657605, 27899486, 26431509, 24915262, 18003757, 12453420, 11162430, 21518407, 32910913) (less)
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Pathogenic
(Feb 01, 2003)
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no assertion criteria provided
Method: literature only
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MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036348.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a 3-generation Norwegian family with MODY3 (600496), Bjorkhaug et al. (2000) found a C-to-T transition at nucleotide 358 in exon 2 of the HNF1A … (more)
In a 3-generation Norwegian family with MODY3 (600496), Bjorkhaug et al. (2000) found a C-to-T transition at nucleotide 358 in exon 2 of the HNF1A gene, leading to a pro112-to-leu (P112L) amino acid substitution, in all 3 affected members. The phenotype in this family was mild with mild fasting and postprandial hyperglycemia easily controlled by diet only. Diabetes-associated late complications were not observed. P112L mutant protein demonstrated a significantly reduced ability to bind a high affinity HNF1 binding site and to activate transcription. Immunolocalization studies in HeLa cells showed that P112L mutant protein was correctly targeted to the nucleus. Bjorkhaug et al. (2000) concluded that the P112L mutation seems to impair pancreatic beta-cell function by loss-of-function mechanisms. Xu et al. (2002) found the HNF1A P112L mutation in a southern Chinese MODY family. Bjorkhaug et al. (2003) found evidence for possible founder effect of the P112L mutation in the Norwegian population. (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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Clinical and genetic characterization and long-term evaluation of individuals with maturity-onset diabetes of the young (MODY): The journey towards appropriate treatment. | Campos Franco P | Diabetes research and clinical practice | 2022 | PMID: 35472491 |
Unsupervised Clustering of Missense Variants in HNF1A Using Multidimensional Functional Data Aids Clinical Interpretation. | Althari S | American journal of human genetics | 2020 | PMID: 32910913 |
New clinical screening strategy to distinguish HNF1A variant-induced diabetes from young early-onset type 2 diabetes in a Chinese population. | Ma Y | BMJ open diabetes research & care | 2020 | PMID: 32238361 |
Functional Investigations of HNF1A Identify Rare Variants as Risk Factors for Type 2 Diabetes in the General Population. | Najmi LA | Diabetes | 2017 | PMID: 27899486 |
High Incidence of Heterozygous ABCC8 and HNF1A Mutations in Czech Patients With Congenital Hyperinsulinism. | Rozenkova K | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 26431509 |
Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population. | SIGMA Type 2 Diabetes Consortium | JAMA | 2014 | PMID: 24915262 |
Persistently autoantibody negative (PAN) type 1 diabetes mellitus in children. | Hameed S | Pediatric diabetes | 2011 | PMID: 21518407 |
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 |
Pancreatic exocrine dysfunction in maturity-onset diabetes of the young type 3. | Vesterhus M | Diabetes care | 2008 | PMID: 17989309 |
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 |
Mutations in the hepatocyte nuclear factor-1alpha gene in Chinese MODY families: prevalence and functional analysis. | Xu JY | Diabetologia | 2002 | PMID: 12107757 |
MODY associated with two novel hepatocyte nuclear factor-1alpha loss-of-function mutations (P112L and Q466X). | Bjørkhaug L | Biochemical and biophysical research communications | 2000 | PMID: 11162430 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/53a9fce0-d78f-477d-9a67-dfcbda28884c | - | - | - | - |
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Text-mined citations for rs137853243 ...
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.