PM1, PM2, PM5, PP2, PP3, PP5
ClinVar Genomic variation as it relates to human health
NM_000458.4(HNF1B):c.443C>T (p.Ser148Leu)
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.
(7)
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
7
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.443C>T (p.Ser148Leu)
Variation ID: 635698 Accession: VCV000635698.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q12 17: 37739541 (GRCh38) [ NCBI UCSC ] 17: 36099532 (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 Jul 15, 2019 Feb 20, 2024 Sep 23, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000458.4:c.443C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000449.1:p.Ser148Leu missense NM_001165923.4:c.443C>T NP_001159395.1:p.Ser148Leu missense NM_001304286.2:c.443C>T NP_001291215.1:p.Ser148Leu missense NC_000017.11:g.37739541G>A NC_000017.10:g.36099532G>A NG_013019.2:g.10566C>T - Protein change
- S148L
- Other names
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- Canonical SPDI
- NC_000017.11:37739540: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.
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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 | ||
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| 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 23, 2022 | RCV001281300.7 | |
| Pathogenic (1) |
no assertion criteria provided
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Apr 18, 2014 | RCV001328307.3 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 11, 2022 | RCV001785725.7 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jan 6, 2022 | RCV002501024.3 |
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
(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: SCV000926139.1
First in ClinVar: Jul 15, 2019 Last updated: Jul 15, 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 PMID:25700310; PMID:15930087; PMID:17116179; PMID:18644064; … (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 PMID:25700310; PMID:15930087; PMID:17116179; PMID:18644064; PMID:18249217; PMID:21380624; PMID:25536396 as "c.443C>T, c.637C>T; c.443C>T" with clinical significance Pathogenic. It has been re-classified using InterVar and manual curation as Pathogenic based on PS2 PS4 PM1 PM2 PM5 PP3. (less)
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Likely pathogenic
(Feb 01, 2020)
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criteria provided, single submitter
Method: research
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Renal cysts and diabetes syndrome
Affected status: yes
Allele origin:
de novo
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Molecular Biology Laboratory, Fundació Puigvert
Study: KidneyPanel_2020
Accession: SCV001425085.1 First in ClinVar: Jan 13, 2021 Last updated: Jan 13, 2021 |
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Pathogenic
(Sep 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Renal cysts and diabetes syndrome
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV002577449.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PM1, PM2, PM5, PP2, PP3, PP5
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Pathogenic
(Jan 06, 2022)
|
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
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002812980.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 10, 2021)
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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: SCV002028191.2
First in ClinVar: Nov 29, 2021 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect … (more)
Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 28215227, 21767339, 26876668, 21380624, 25741167, 18249217, 23306198, 28844315, 15930087, 31844813, 31825128, 28324003, 33663443, 32708349, 33532864) (less)
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Pathogenic
(Jul 11, 2022)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003017995.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt HNF1B protein function. ClinVar contains an entry for this variant (Variation ID: 635698). This missense change has been observed in individual(s) with renal cysts and diabetes syndrome (PMID: 15930087, 18249217, 21380624, 31825128, 32708349, 33663443). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 148 of the HNF1B protein (p.Ser148Leu). (less)
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Pathogenic
(Apr 18, 2014)
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no assertion criteria provided
Method: clinical testing
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Congenital anomaly of kidney and urinary tract
Affected status: yes
Allele origin:
unknown
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Sydney Genome Diagnostics, Children's Hospital Westmead
Accession: SCV001449330.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This patient is heterozygous for a de novo pathogenic variant, c. 443C>T (p.Ser148Leu), in the HNF1B gene. This variant was initially reported in a 13yo … (more)
This patient is heterozygous for a de novo pathogenic variant, c. 443C>T (p.Ser148Leu), in the HNF1B gene. This variant was initially reported in a 13yo with renal dysplasia (diagnosed at birth) and diabetes (Edghill et al., J Med Genet 2006;43:84-90). It has subsequently been reported as a common cause of renal hypodysplasia (Thomas et al., Pediatr Nephrol, 2011; 26: 897-903) and has also been reported in a 3 month old Turkish child with bilateral hypoplastic kidneys and renal failure (Gonc et al., Paediatric Diabetes, 2012: 13: e1-e5). Testing of parental samples have indicated that this variant is de novo in this patient which adds further support for the pathogenicity of this variant (see MG-14-06539 and MG-14-06540). (less)
Number of individuals with the variant: 1
|
Comment:
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 28215227, 21767339, 26876668, 21380624, 25741167, 18249217, 23306198, 28844315, 15930087, 31844813, 31825128, 28324003, 33663443, 32708349, 33532864)
Comment:
For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt HNF1B protein function. ClinVar contains an entry for this variant (Variation ID: 635698). This missense change has been observed in individual(s) with renal cysts and diabetes syndrome (PMID: 15930087, 18249217, 21380624, 31825128, 32708349, 33663443). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 148 of the HNF1B protein (p.Ser148Leu).
Comment:
This patient is heterozygous for a de novo pathogenic variant, c. 443C>T (p.Ser148Leu), in the HNF1B gene. This variant was initially reported in a 13yo with renal dysplasia (diagnosed at birth) and diabetes (Edghill et al., J Med Genet 2006;43:84-90). It has subsequently been reported as a common cause of renal hypodysplasia (Thomas et al., Pediatr Nephrol, 2011; 26: 897-903) and has also been reported in a 3 month old Turkish child with bilateral hypoplastic kidneys and renal failure (Gonc et al., Paediatric Diabetes, 2012: 13: e1-e5). Testing of parental samples have indicated that this variant is de novo in this patient which adds further support for the pathogenicity of this variant (see MG-14-06539 and MG-14-06540).
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:
PM1, PM2, PM5, PP2, PP3, PP5
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 28215227, 21767339, 26876668, 21380624, 25741167, 18249217, 23306198, 28844315, 15930087, 31844813, 31825128, 28324003, 33663443, 32708349, 33532864)
Comment:
For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt HNF1B protein function. ClinVar contains an entry for this variant (Variation ID: 635698). This missense change has been observed in individual(s) with renal cysts and diabetes syndrome (PMID: 15930087, 18249217, 21380624, 31825128, 32708349, 33663443). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 148 of the HNF1B protein (p.Ser148Leu).
Comment:
This patient is heterozygous for a de novo pathogenic variant, c. 443C>T (p.Ser148Leu), in the HNF1B gene. This variant was initially reported in a 13yo with renal dysplasia (diagnosed at birth) and diabetes (Edghill et al., J Med Genet 2006;43:84-90). It has subsequently been reported as a common cause of renal hypodysplasia (Thomas et al., Pediatr Nephrol, 2011; 26: 897-903) and has also been reported in a 3 month old Turkish child with bilateral hypoplastic kidneys and renal failure (Gonc et al., Paediatric Diabetes, 2012: 13: e1-e5). Testing of parental samples have indicated that this variant is de novo in this patient which adds further support for the pathogenicity of this variant (see MG-14-06539 and MG-14-06540).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players. | Domingo-Gallego A | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2022 | PMID: 33532864 |
| Etiologic distribution and clinical characteristics of pediatric diabetes in 276 children and adolescents with diabetes at a single academic center. | Kim JH | BMC pediatrics | 2021 | PMID: 33663443 |
| Genotype and Phenotype Analyses in Pediatric Patients with HNF1B Mutations. | Lim SH | Journal of clinical medicine | 2020 | PMID: 32708349 |
| A cross-sectional study of patients referred for HNF1B-MODY genetic testing due to cystic kidneys and diabetes. | Sztromwasser P | Pediatric diabetes | 2020 | PMID: 31825128 |
| 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 |
| HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort. | Thomas R | Pediatric nephrology (Berlin, Germany) | 2011 | PMID: 21380624 |
| Lack of pancreatic body and tail in HNF1B mutation carriers. | Haldorsen IS | Diabetic medicine : a journal of the British Diabetic Association | 2008 | PMID: 18644064 |
| Phenotype of a patient with a de novo mutation in the hepatocyte nuclear factor 1beta/maturity-onset diabetes of the young type 5 gene. | Mayer C | Metabolism: clinical and experimental | 2008 | PMID: 18249217 |
| Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1beta in human pancreatic development. | Edghill EL | Diabetic medicine : a journal of the British Diabetic Association | 2006 | PMID: 17116179 |
| Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. | Edghill EL | Journal of medical genetics | 2006 | PMID: 15930087 |
| - | - | - | - | 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.