ClinVar Genomic variation as it relates to human health
NM_000545.8(HNF1A):c.392G>A (p.Arg131Gln)
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.392G>A (p.Arg131Gln)
Variation ID: 562373 Accession: VCV000562373.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 120988898 (GRCh38) [ NCBI UCSC ] 12: 121426701 (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 1, 2018 Feb 14, 2024 Aug 11, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000545.8:c.392G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000536.6:p.Arg131Gln missense NM_000545.6(HNF1A):c.392G>A NM_001306179.2:c.392G>A NP_001293108.2:p.Arg131Gln missense NC_000012.12:g.120988898G>A NC_000012.11:g.121426701G>A NG_011731.2:g.15153G>A LRG_522:g.15153G>A LRG_522t1:c.392G>A - Protein change
- R131Q
- Other names
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- Canonical SPDI
- NC_000012.12:120988897:G:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- 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
Help
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
Help
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 (4) |
criteria provided, multiple submitters, no conflicts
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Oct 30, 2023 | RCV000681832.9 | |
Pathogenic (2) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001248948.5 | |
Pathogenic (1) |
reviewed by expert panel
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Aug 11, 2021 | RCV001796178.3 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV002464290.1 |
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
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
(Aug 11, 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: SCV002032344.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
Comment:
The c.392G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 131 (p.(R131Q)) of NM_000545.8. … (more)
The c.392G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 131 (p.(R131Q)) of NM_000545.8. This variant has a minor allele frequency of 0.000008795 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (=0.00002 and =1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, which is greater than the MDEP threshold of 0.70 (PP3), which is supported by functional studies that demonstrated the p.Arg131Gln protein has abnormal nuclear localization and transactivation below 40% of wildtype (PMID: 32910913 and PMID: 10585442) (PS3_Supporting). This variant resides in an amino acid within the HNF1a DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in at least 40 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:9287053, PMID:10447526, PMID:894547, PMID:9032114, PMID:1115175, PMID:11315851, PMID:12442290, PMID:162495, PMID:19754856, PMID:2095039, ClinVar ID: 562373, internal lab contributors). This variant segregated with diabetes, with at least 20 informative meioses in 6 families with MODY (PP1_Strong; PMID:10447526, PMID:894547, PMID:9032114, PMID:11315851, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in 2 individuals with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator results <50%)(PS2; PMID:24323243). Additionally, at least 2 individuals have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP: PP1_Strong, PS2, PS4, PP4_Moderate, PM1, PP3, PM2_Supporting, PS3_Supporting. (less)
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Pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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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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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422727.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Arg131Gln variant in HNF1A has been reported in at least 15 individuals with maturity-onset diabetes of the young, segregated with disease in 4 affected … (more)
The p.Arg131Gln variant in HNF1A has been reported in at least 15 individuals with maturity-onset diabetes of the young, segregated with disease in 4 affected relatives from 2 families (PMID: 24323243, 12442280, 22060211, 17937063, 18838325, 11315851, 9032114, 9287053, 18003757), but has been identified in 0.0009% (1/113698) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753998395). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic by Columbia University in ClinVar (Variation ID: 562373). In vitro functional studies provide some evidence that the p.Arg131Gln variant may slightly impact protein function (PMID: 27899486). 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.Arg131Gln variant 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: 28410371). In summary, this variant meets criteria to be classified as pathogenic for maturity-onset diabetes of the young in an autosomal dominant manner based on more affected individuals with the variant than expected, low frequency in the general population, location in a functional domain, and in vitro functional studies. ACMG/AMP Criteria applied: PS4, PM2, PM1, PP3, PP1, PS3_Supporting (Richards 2015). (less)
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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: SCV002605480.1
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 rs753998395 with MODY3. (less)
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Pathogenic
(Oct 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: SCV002770448.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been … (more)
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple individuals with clinical features associated with this gene, including multiple de novo occurrences. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant shows reduced transcriptional activity compared to wildtype in multiple cell lines (PMID: 23607861, 27899486, 32910913). The variant is located in a region that is considered important for protein function and/or structure. (less)
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Pathogenic
(Oct 30, 2023)
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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: SCV001803365.2
First in ClinVar: Aug 21, 2021 Last updated: Nov 25, 2023 |
Comment:
Published functional studies demonstrate decreased target promoter activity compared to wildtype (PMID: 23607861); Not observed at significant frequency in large population cohorts (gnomAD); In silico … (more)
Published functional studies demonstrate decreased target promoter activity compared to wildtype (PMID: 23607861); 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: 24097065, 29927023, 28012402, 21761282, 34462253, 30586318, 25414397, 8945470, 27899486, 28410371, 11058894, 12442280, 18838325, 18513302, 27634015, 19754856, 30754156, 12453420, 17937063, 30754209, 23607861, 22060211, 34108472, 18003757, 36227502, 24323243) (less)
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Pathogenic
(Apr 06, 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: SCV003293543.2
First in ClinVar: Feb 07, 2023 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: 27899486). 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: 27899486). 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: 562373). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 8945470). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs753998395, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 131 of the HNF1A protein (p.Arg131Gln). (less)
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Pathogenic
(Sep 16, 2018)
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no assertion criteria provided
Method: research
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not provided
Affected status: yes
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000809307.1
First in ClinVar: Oct 01, 2018 Last updated: Oct 01, 2018 |
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Pathogenic
(-)
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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:
unknown
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Genomics And Bioinformatics Analysis Resource, Columbia University
Accession: SCV004024126.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
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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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Genetic and Clinical Characterization of Patients with Maturity-Onset of Diabetes of the Young (MODY): Identification of Novel Variations. | Ateş EA | Balkan medical journal | 2021 | PMID: 34462253 |
Unsupervised Clustering of Missense Variants in HNF1A Using Multidimensional Functional Data Aids Clinical Interpretation. | Althari S | American journal of human genetics | 2020 | PMID: 32910913 |
Genetic basis of early-onset, maturity-onset diabetes of the young-like diabetes in Japan and features of patients without mutations in the major MODY genes: Dominance of maternal inheritance. | Yorifuji T | Pediatric diabetes | 2018 | PMID: 29927023 |
Comprehensive screening for monogenic diabetes in 89 Japanese children with insulin-requiring antibody-negative type 1 diabetes. | Ushijima K | Pediatric diabetes | 2018 | PMID: 28597946 |
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 |
Functional Investigations of HNF1A Identify Rare Variants as Risk Factors for Type 2 Diabetes in the General Population. | Najmi LA | Diabetes | 2017 | PMID: 27899486 |
Low prevalence of HNF1A mutations after molecular screening of multiple MODY genes in 58 Italian families recruited in the pediatric or adult diabetes clinic from a single Italian hospital. | Delvecchio M | Diabetes care | 2014 | PMID: 25414397 |
De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed. | Stanik J | Diabetologia | 2014 | PMID: 24323243 |
Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. | Flannick J | Nature genetics | 2013 | PMID: 24097065 |
Alterations in bile acid synthesis in carriers of hepatocyte nuclear factor 1α mutations. | Ekholm E | Journal of internal medicine | 2013 | PMID: 23607861 |
Metabolite profiling reveals normal metabolic control in carriers of mutations in the glucokinase gene (MODY2). | Spégel P | Diabetes | 2013 | PMID: 23139355 |
Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus. | Yorifuji T | Pediatric diabetes | 2012 | PMID: 22060211 |
Molecular background and clinical characteristics of HNF1A MODY in a Polish population. | Skupien J | Diabetes & metabolism | 2008 | PMID: 18838325 |
Can complement factors 5 and 8 and transthyretin be used as biomarkers for MODY 1 (HNF4A-MODY) and MODY 3 (HNF1A-MODY)? | Karlsson E | Diabetic medicine : a journal of the British Diabetic Association | 2008 | PMID: 18513302 |
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 |
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 |
Mechanisms of mutual functional interactions between HNF-4alpha and HNF-1alpha revealed by mutations that cause maturity onset diabetes of the young. | Rowley CW | American journal of physiology. Gastrointestinal and liver physiology | 2006 | PMID: 16223942 |
Spectrum of HNF1A and GCK mutations in Canadian families with maturity-onset diabetes of the young (MODY). | McKinney JL | Clinical and investigative medicine. Medecine clinique et experimentale | 2004 | PMID: 15305805 |
HNF-1alpha and endodermal transcription factors cooperatively activate Fabpl: MODY3 mutations abrogate cooperativity. | Divine JK | American journal of physiology. Gastrointestinal and liver physiology | 2003 | PMID: 12646418 |
Diabetes mutations delineate an atypical POU domain in HNF-1alpha. | Chi YI | Molecular cell | 2002 | PMID: 12453420 |
GCK and HNF1A mutations in Canadian families with maturity onset diabetes of the young (MODY). | Cao H | Human mutation | 2002 | PMID: 12442280 |
Contribution of known and unknown susceptibility genes to early-onset diabetes in scandinavia: evidence for heterogeneity. | Lindgren CM | Diabetes | 2002 | PMID: 11978663 |
Prevalence of maturity-onset diabetes of the young mutations in Brazilian families with autosomal-dominant early-onset type 2 diabetes. | Moises RS | Diabetes care | 2001 | PMID: 11315851 |
Anatomy of a homeoprotein revealed by the analysis of human MODY3 mutations. | Vaxillaire M | The Journal of biological chemistry | 1999 | PMID: 10585442 |
High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes. | Lehto M | Diabetologia | 1999 | PMID: 10447526 |
Molecular genetics of MODY in Germany. | Lindner TH | Diabetologia | 1999 | PMID: 10027594 |
Mutations in the hepatocyte nuclear factor-1alpha/MODY3 gene in Japanese subjects with early- and late-onset NIDDM. | Iwasaki N | Diabetes | 1997 | PMID: 9287053 |
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 |
Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). | Yamagata K | Nature | 1996 | PMID: 8945470 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1c241a8b-e5cd-4a72-a5e4-95225233cb19 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/650e4d16-b761-4c10-ac4d-479b2c98013e | - | - | - | - |
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Text-mined citations for rs753998395 ...
HelpRecord last updated Mar 30, 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.