This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ClinVar Genomic variation as it relates to human health
NM_000545.8(HNF1A):c.1501+7G>A
Germline
Classification
Help
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.
(11)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(8)
Uncertain significance(1); Benign(8)
11
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000545.8(HNF1A):c.1501+7G>A
Variation ID: 129231 Accession: VCV000129231.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 120997672 (GRCh38) [ NCBI UCSC ] 12: 121435475 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 9, 2014 May 1, 2024 Feb 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000545.8:c.1501+7G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001306179.2:c.1501+7G>A intron variant NC_000012.12:g.120997672G>A NC_000012.11:g.121435475G>A NG_011731.2:g.23927G>A LRG_522:g.23927G>A LRG_522t1:c.1501+7G>A - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000012.12:120997671:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.35962 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.30441
Trans-Omics for Precision Medicine (TOPMed) 0.30861
1000 Genomes Project 30x 0.35025
1000 Genomes Project 0.35962
The Genome Aggregation Database (gnomAD), exomes 0.38982
Exome Aggregation Consortium (ExAC) 0.43472
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.29006
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
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. |
|||
| HNF1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
911 | 1002 | |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Benign (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 22, 2013 | RCV000117228.18 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 10, 2021 | RCV000377703.10 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000710266.13 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
- | RCV002226668.4 | |
| Benign (1) |
criteria provided, single submitter
|
Dec 8, 2014 | RCV002390266.4 | |
| Benign (1) |
criteria provided, single submitter
|
Jul 7, 2023 | RCV003315670.3 |
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
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
Help
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. |
|
|---|---|---|---|---|---|
|
Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000305099.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
|
Benign
(Oct 22, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000168826.9
First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
|
|
Benign
(Jul 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000613600.2
First in ClinVar: Oct 02, 2016 Last updated: Oct 20, 2018 |
|
|
|
Benign
(Aug 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity-onset diabetes of the young type 3
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001933072.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001725686.4
First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024 |
|
|
|
Benign
(Dec 08, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002700564.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
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Benign
(Jan 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity-onset diabetes of the young type 3
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000376721.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: research
|
Type 2 diabetes mellitus
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
maternal
|
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002505645.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Comment:
Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially multiple cardiovascular complications. Associated with … (more)
Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially multiple cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, no sufficient evidence is found to support association of rs2464195 with T2DM or MODY. (less)
|
|
|
Benign
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Nonpapillary renal cell carcinoma
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004015758.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
|
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
AllHighlyPenetrant
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000151401.2
First in ClinVar: May 17, 2014 Last updated: Jul 06, 2014 |
Comment:
Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated … (more)
Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. (less)
|
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000083913.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
|
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Comment:
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Comment:
Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially multiple cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, no sufficient evidence is found to support association of rs2464195 with T2DM or MODY.
Comment:
Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
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. |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Comment:
Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially multiple cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, no sufficient evidence is found to support association of rs2464195 with T2DM or MODY.
Comment:
Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genome-wide Association Analysis of Proinflammatory Cytokines and Gene-lifestyle Interaction for Invasive Breast Cancer Risk: The WHI dbGaP Study. | Jung SY | Cancer prevention research (Philadelphia, Pa.) | 2021 | PMID: 32928877 |
| Common coding variants of the HNF1A gene are associated with multiple cardiovascular risk phenotypes in community-based samples of younger and older European-American adults: the Coronary Artery Risk Development in Young Adults Study and The Cardiovascular Health Study. | Reiner AP | Circulation. Cardiovascular genetics | 2009 | PMID: 20031592 |
| Mutations of maturity-onset diabetes of the young (MODY) genes in Thais with early-onset type 2 diabetes mellitus. | Plengvidhya N | Clinical endocrinology | 2009 | PMID: 18811724 |
| 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 |
| Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain. | Estalella I | Clinical endocrinology | 2007 | PMID: 17573900 |
| [The genetic and clinical characteristics of transcription factor 1 gene mutations in Chinese diabetes]. | Yang Z | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2007 | PMID: 17407072 |
| GCK and HNF1alpha mutations and polymorphisms in Polish women with gestational diabetes. | Zurawek M | Diabetes research and clinical practice | 2007 | PMID: 16963153 |
| Transcription factors regulating beta-cell function. | Cerf ME | European journal of endocrinology | 2006 | PMID: 17062882 |
| 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 |
| Mutations in MODY genes are not common cause of early-onset type 2 diabetes in Mexican families. | Domínguez-López A | JOP : Journal of the pancreas | 2005 | PMID: 15883474 |
| Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes HNF-4alpha, GCK and HNF-1alpha. | Pruhova S | Diabetologia | 2003 | PMID: 12627330 |
| Hepatocyte nuclear factor-1 alpha gene mutations and diabetes in Norway. | Bjørkhaug L | The Journal of clinical endocrinology and metabolism | 2003 | PMID: 12574234 |
| Identification and functional analysis of mutations in the hepatocyte nuclear factor-1alpha gene in anti-islet autoantibody-negative Japanese patients with type 1 diabetes. | Kawasaki E | The Journal of clinical endocrinology and metabolism | 2000 | PMID: 10634407 |
| Molecular genetics of diabetes mellitus in Chinese subjects: identification of mutations in glucokinase and hepatocyte nuclear factor-1alpha genes in patients with early-onset type 2 diabetes mellitus/MODY. | Ng MC | Diabetic medicine : a journal of the British Diabetic Association | 1999 | PMID: 10588527 |
| Mutations in the hepatocyte nuclear factor-1alpha/MODY3 gene in Japanese subjects with early- and late-onset NIDDM. | Iwasaki N | Diabetes | 1997 | PMID: 9287053 |
| Genetic variation in the hepatocyte nuclear factor-1 alpha gene in Danish Caucasians with late-onset NIDDM. | Urhammer SA | Diabetologia | 1997 | PMID: 9112026 |
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Text-mined citations for rs2464195 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.