For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 36849). This variant is also known as P159fsdelT. This premature translational stop signal has been observed in individual(s) with clinical features of HNF1B-related conditions (PMID: 11085914, 24429398). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met160*) in the HNF1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1B are known to be pathogenic (PMID: 9398836, 12148114, 15068978, 20378641).
ClinVar Genomic variation as it relates to human health
NM_000458.4(HNF1B):c.477del (p.Pro159_Met160insTer)
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.
(5)
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.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000458.4(HNF1B):c.477del (p.Pro159_Met160insTer)
Variation ID: 36849 Accession: VCV000036849.10
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 17q12 17: 37739507 (GRCh38) [ NCBI UCSC ] 17: 36099498 (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 Apr 4, 2013 Jul 23, 2024 Sep 2, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000458.4:c.477del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000449.1:p.Pro159_Met160insTer frameshift NM_000458.3:c.477delT NM_001165923.4:c.477del NP_001159395.1:p.Pro159_Met160insTer frameshift NM_001304286.2:c.477del NP_001291215.1:p.Pro159_Met160insTer frameshift NC_000017.11:g.37739507del NC_000017.10:g.36099498del NG_013019.2:g.10600del - Protein change
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- Other names
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- Canonical SPDI
- NC_000017.11:37739506: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.
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- 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. |
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| 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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 2, 2022 | RCV000030530.9 | |
| Pathogenic (1) |
criteria provided, single submitter
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Dec 19, 2021 | RCV002513268.5 | |
| Pathogenic (1) |
criteria provided, single submitter
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Dec 3, 2021 | RCV002477029.3 |
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. |
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Pathogenic
(Dec 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Type 2 diabetes mellitus
Renal cysts and diabetes syndrome Nonpapillary renal cell carcinoma
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002777640.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003443072.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 36849). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 36849). This variant is also known as P159fsdelT. This premature translational stop signal has been observed in individual(s) with clinical features of HNF1B-related conditions (PMID: 11085914, 24429398). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met160*) in the HNF1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1B are known to be pathogenic (PMID: 9398836, 12148114, 15068978, 20378641). (less)
|
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Pathogenic
(Sep 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Renal cysts and diabetes syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766951.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function, and gain … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function, and gain of function are all reported mechanisms of disease in this gene and are associated with type 2 diabetes mellitus (MIM#125853) and renal cysts and diabetes syndrome (MIM#137920; OMIM, PMID: 25536396, 11845238, 15509593). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is significant interfamilial and intrafamilial variability of HNF1B-related nephropathy (PMID: 33305128). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in indidivuals with diabetes mellitus, noninsulin-dependent (MODY) or glomerulocystic kidney disease (ClinVar, PMID: 11085914, PMID: 30259503). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jul 06, 2019)
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criteria provided, single submitter
Method: literature only
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Renal cysts and diabetes syndrome
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV000926130.1
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 ClinVar:12639; ClinVar:36849; PMID:25700310; PMID:11085914; … (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 ClinVar:12639; ClinVar:36849; PMID:25700310; PMID:11085914; PMID:24429398; PMID:11085914; PMID:30259503; PMID:25536396 as "HNF1B, 1-BP DEL (P159fsdelT); NM_000458.3(HNF1B):c.477delT (p.Met160Terfs); c.477delT; c.477delT p.M160*; c.477delT p.Met160Terfs; c.477delT" with clinical significance Pathogenic; Likely pathogenic. It has been re-classified using InterVar and manual curation as Pathogenic based on PVS1 PM2 PP3. (less)
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likely pathogenic
(Aug 18, 2011)
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criteria provided, single submitter
Method: curation, clinical testing
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MODY5/RCAD
(autosomal dominant)
Affected status: unknown, yes
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053201.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 07, 2022 |
Comment:
Converted during submission to Likely pathogenic.
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Tissue: Blood
|
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function, and gain of function are all reported mechanisms of disease in this gene and are associated with type 2 diabetes mellitus (MIM#125853) and renal cysts and diabetes syndrome (MIM#137920; OMIM, PMID: 25536396, 11845238, 15509593). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is significant interfamilial and intrafamilial variability of HNF1B-related nephropathy (PMID: 33305128). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in indidivuals with diabetes mellitus, noninsulin-dependent (MODY) or glomerulocystic kidney disease (ClinVar, PMID: 11085914, PMID: 30259503). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Converted during submission to Likely pathogenic.
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:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 36849). This variant is also known as P159fsdelT. This premature translational stop signal has been observed in individual(s) with clinical features of HNF1B-related conditions (PMID: 11085914, 24429398). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met160*) in the HNF1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1B are known to be pathogenic (PMID: 9398836, 12148114, 15068978, 20378641).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function, and gain of function are all reported mechanisms of disease in this gene and are associated with type 2 diabetes mellitus (MIM#125853) and renal cysts and diabetes syndrome (MIM#137920; OMIM, PMID: 25536396, 11845238, 15509593). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is significant interfamilial and intrafamilial variability of HNF1B-related nephropathy (PMID: 33305128). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in indidivuals with diabetes mellitus, noninsulin-dependent (MODY) or glomerulocystic kidney disease (ClinVar, PMID: 11085914, PMID: 30259503). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Converted during submission to Likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Variable Expressivity of HNF1B Nephropathy, From Renal Cysts and Diabetes to Medullary Sponge Kidney Through Tubulo-interstitial Kidney Disease. | Izzi C | Kidney international reports | 2020 | PMID: 33305128 |
| The importance of combined NGS and MLPA genetic tests for differential diagnosis of maturity onset diabetes of the young. | Komazec J | Endokrynologia Polska | 2019 | PMID: 30259503 |
| 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 |
| Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. | Hwang DY | Kidney international | 2014 | PMID: 24429398 |
| Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. | Heidet L | Clinical journal of the American Society of Nephrology : CJASN | 2010 | PMID: 20378641 |
| A genetic syndrome of chronic renal failure with multiple renal cysts and early onset diabetes. | Thomas CP | Kidney international | 2008 | PMID: 18528323 |
| HNF1beta/TCF2 mutations impair transactivation potential through altered co-regulator recruitment. | Barbacci E | Human molecular genetics | 2004 | PMID: 15509593 |
| Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. | Bellanné-Chantelot C | Annals of internal medicine | 2004 | PMID: 15068978 |
| Renal cysts and diabetes syndrome linked to mutations of the hepatocyte nuclear factor-1 beta gene: description of a new family with associated liver involvement. | Montoli A | American journal of kidney diseases : the official journal of the National Kidney Foundation | 2002 | PMID: 12148114 |
| Identification of a gain-of-function mutation in the HNF-1beta gene in a Japanese family with MODY. | Yoshiuchi I | Diabetologia | 2002 | PMID: 11845238 |
| Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease. | Bingham C | American journal of human genetics | 2001 | PMID: 11085914 |
| Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. | Horikawa Y | Nature genetics | 1997 | PMID: 9398836 |
| - | - | - | - | DOI: 10.1101/576918 |
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Text-mined citations for this variant ...
HelpRecord 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.