Identified in multiple patients with structural renal abnormalities, however, family segregation studies have been limited, functional studies have not been performed, and only the HNF1B gene was sequenced in most publications (Ulinski et al., 2006; Nakayama et al., 2010; Musetti et al., 2014, Raaijmakers et al., 2015; Okorn et al., 2019); Identified in an individual with maturity-onset diabetes of the young, however, additional clinical and segregation information was not provided (Bellanne-Chatelot et al., 2005); Identified in randomly selected individuals from the Framingham and Jackson Heart Studies (Flannick et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21775974, 24097065, 24387224, 20155289, 26764160, 25500806, 16249435, 30666461, 16371430, 31365591, 34426522, 33324081)
ClinVar Genomic variation as it relates to human health
NM_000458.4(HNF1B):c.226G>T (p.Gly76Cys)
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.
(14)
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(4); Likely benign(6)
Uncertain significance(4); Likely benign(6)
14
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000458.4(HNF1B):c.226G>T (p.Gly76Cys)
Variation ID: 193102 Accession: VCV000193102.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q12 17: 37744659 (GRCh38) [ NCBI UCSC ] 17: 36104650 (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 28, 2015 Nov 24, 2024 Jan 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000458.4:c.226G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000449.1:p.Gly76Cys missense NM_001165923.4:c.226G>T NP_001159395.1:p.Gly76Cys missense NM_001304286.2:c.226G>T NP_001291215.1:p.Gly76Cys missense NC_000017.11:g.37744659C>A NC_000017.10:g.36104650C>A NG_013019.2:g.5448G>T P35680:p.Gly76Cys - Protein change
- G76C
- Other names
-
NM_000458.3(HNF1B):c.226G>T(p.Gly76Cys)
NM_001165923.3(HNF1B):c.226G>T(p.Gly76Cys)
NM_001304286.1(HNF1B):c.226G>T(p.Gly76Cys)
- Canonical SPDI
- NC_000017.11:37744658:C: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| HNF1B | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
638 | 855 | |
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. |
|---|---|---|---|---|
| Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
May 22, 2023 | RCV000173138.6 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Jul 6, 2019 | RCV000369522.10 | |
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jan 16, 2024 | RCV000993276.13 | |
| Likely benign (1) |
no assertion criteria provided
|
Oct 25, 2018 | RCV001328309.1 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jul 7, 2023 | RCV003316074.1 | |
|
HNF1B-related disorder
|
Likely benign (1) |
no assertion criteria provided
|
Jan 29, 2020 | RCV003947459.2 |
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. |
|
|---|---|---|---|---|---|
|
Likely benign
(Nov 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV001146113.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
|
|
|
Uncertain significance
(Mar 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002552723.2
First in ClinVar: Jul 29, 2022 Last updated: Mar 04, 2023 |
Comment:
Identified in multiple patients with structural renal abnormalities, however, family segregation studies have been limited, functional studies have not been performed, and only the HNF1B … (more)
Identified in multiple patients with structural renal abnormalities, however, family segregation studies have been limited, functional studies have not been performed, and only the HNF1B gene was sequenced in most publications (Ulinski et al., 2006; Nakayama et al., 2010; Musetti et al., 2014, Raaijmakers et al., 2015; Okorn et al., 2019); Identified in an individual with maturity-onset diabetes of the young, however, additional clinical and segregation information was not provided (Bellanne-Chatelot et al., 2005); Identified in randomly selected individuals from the Framingham and Jackson Heart Studies (Flannick et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21775974, 24097065, 24387224, 20155289, 26764160, 25500806, 16249435, 30666461, 16371430, 31365591, 34426522, 33324081) (less)
|
|
|
Likely benign
(May 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934525.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
|
|
|
Uncertain significance
(Nov 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005412706.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
BS1, PP3
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(May 31, 2018)
|
criteria provided, single submitter
Method: curation
|
Renal cysts and diabetes syndrome
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803619.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Renal cysts and diabetes syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) … (more)
This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Renal cysts and diabetes syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder (PMID:23539225). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. (less)
|
|
|
Likely benign
(Jun 04, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000224227.5
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Uncertain significance
(Jul 06, 2019)
|
criteria provided, single submitter
Method: literature only
|
Renal cysts and diabetes syndrome
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV000926175.1
First in ClinVar: Jul 14, 2019 Last updated: Jul 14, 2019
Comment:
This variant and it's classification has been reported by Vasileiou et al. 2019; DOI:10.1101/576918. The variants has previously been reported in LOVD:#0000325358; PMID:25700310; PMID:16371430; PMID:16249435; … (more)
This variant and it's classification has been reported by Vasileiou et al. 2019; DOI:10.1101/576918. The variants has previously been reported in LOVD:#0000325358; PMID:25700310; PMID:16371430; PMID:16249435; PMID:24387224; PMID:25500806; PMID:25536396 as "HNF1B:NM_000458.2:c.226G>T; c.226G>T; c.G226T p.Gly76Cys; E1: c.226G>T (p.Gly76Cys) (INH) ; c.226G>T" with clinical significance Likely pathogenic; Pathogenic. It has been re-classified using InterVar and manual curation as Uncertain significance based on PM1 PP3 PP5 BP6. (less)
|
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Renal cysts and diabetes syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000402435.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Likely 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: SCV004015773.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
|
|
|
Likely benign
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002421538.3
First in ClinVar: Apr 08, 2022 Last updated: Feb 20, 2024 |
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002033909.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Likely benign
(Oct 25, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Congenital anomaly of kidney and urinary tract
Affected status: yes
Allele origin:
unknown
|
Sydney Genome Diagnostics, Children's Hospital Westmead
Accession: SCV001449332.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Number of individuals with the variant: 1
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036456.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Likely benign
(Jan 29, 2020)
|
no assertion criteria provided
Method: clinical testing
|
HNF1B-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004760606.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
BS1, PP3
Comment:
This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Renal cysts and diabetes syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder (PMID:23539225). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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:
Identified in multiple patients with structural renal abnormalities, however, family segregation studies have been limited, functional studies have not been performed, and only the HNF1B gene was sequenced in most publications (Ulinski et al., 2006; Nakayama et al., 2010; Musetti et al., 2014, Raaijmakers et al., 2015; Okorn et al., 2019); Identified in an individual with maturity-onset diabetes of the young, however, additional clinical and segregation information was not provided (Bellanne-Chatelot et al., 2005); Identified in randomly selected individuals from the Framingham and Jackson Heart Studies (Flannick et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21775974, 24097065, 24387224, 20155289, 26764160, 25500806, 16249435, 30666461, 16371430, 31365591, 34426522, 33324081)
Comment:
BS1, PP3
Comment:
This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Renal cysts and diabetes syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder (PMID:23539225). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Maturity-Onset Diabetes of the Young Identified Among Algerian Probands with Early-Onset Diabetes. | Bouldjennet F | Diabetes, metabolic syndrome and obesity : targets and therapy | 2020 | PMID: 33324081 |
| Targeted sequencing identifies novel variants in common and rare MODY genes. | de Santana LS | Molecular genetics & genomic medicine | 2019 | PMID: 31595705 |
| Negative autoimmunity in a Spanish pediatric cohort suspected of type 1 diabetes, could it be monogenic diabetes? | Urrutia I | PloS one | 2019 | PMID: 31365591 |
| Characteristics of maturity onset diabetes of the young in a large diabetes center. | Chambers C | Pediatric diabetes | 2016 | PMID: 26059258 |
| Molecular diagnosis of maturity-onset diabetes of the young (MODY) in Turkish children by using targeted next-generation sequencing. | Anık A | Journal of pediatric endocrinology & metabolism : JPEM | 2015 | PMID: 26226118 |
| Simplified screening criteria for HNF1B analysis. | Raaijmakers AA | Kidney international | 2015 | PMID: 26024028 |
| A novel mutation of the HNF1B gene associated with hypoplastic glomerulocystic kidney disease and neonatal renal failure: a case report and mutation update. | Alvelos MI | Medicine | 2015 | PMID: 25700310 |
| HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum. | Clissold RL | Nature reviews. Nephrology | 2015 | PMID: 25536396 |
| Criteria for HNF1B analysis in patients with congenital abnormalities of kidney and urinary tract. | Raaijmakers A | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2015 | PMID: 25500806 |
| Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy. | Quaglia M | Clinical transplantation | 2014 | PMID: 24961278 |
| The HNF1B score is a simple tool to select patients for HNF1B gene analysis. | Faguer S | Kidney international | 2014 | PMID: 24897035 |
| Chronic renal failure of unknown origin is caused by HNF1B mutations in 9% of adult patients: a single centre cohort analysis. | Musetti C | Nephrology (Carlton, Vic.) | 2014 | PMID: 24387224 |
| Severe prenatal renal anomalies associated with mutations in HNF1B or PAX2 genes. | Madariaga L | Clinical journal of the American Society of Nephrology : CJASN | 2013 | PMID: 23539225 |
| Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood. | Faguer S | Kidney international | 2011 | PMID: 21775974 |
| HNF1B alterations associated with congenital anomalies of the kidney and urinary tract. | Nakayama M | Pediatric nephrology (Berlin, Germany) | 2010 | PMID: 20155289 |
| Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort. | Ulinski T | Journal of the American Society of Nephrology : JASN | 2006 | PMID: 16371430 |
| Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. | Bellanné-Chantelot C | Diabetes | 2005 | PMID: 16249435 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HNF1B | - | - | - | - |
| - | - | - | - | DOI: 10.1101/576918 |
| click to load more click to collapse | ||||
Text-mined citations for this variant ...
HelpRecord last updated Nov 25, 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.