ClinVar Genomic variation as it relates to human health
NM_000545.8(HNF1A):c.526C>T (p.Gln176Ter)
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.526C>T (p.Gln176Ter)
Variation ID: 372380 Accession: VCV000372380.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 120989032 (GRCh38) [ NCBI UCSC ] 12: 121426835 (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 Jan 9, 2017 Apr 20, 2024 Apr 10, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000545.8:c.526C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000536.6:p.Gln176Ter nonsense NM_000545.6(HNF1A):c.526C>T NM_001306179.2:c.526C>T NP_001293108.2:p.Gln176Ter nonsense NC_000012.12:g.120989032C>T NC_000012.11:g.121426835C>T NG_011731.2:g.15287C>T LRG_522:g.15287C>T LRG_522t1:c.526C>T - Protein change
- Q176*
- Other names
- NM_000545.8(HNF1A):c.526C>T
- Canonical SPDI
- NC_000012.12:120989031:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- protein loss of function Variation Ontology [VariO:0043]
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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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 27, 2023 | RCV000414498.11 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 2, 2022 | RCV001249012.9 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 7, 2021 | RCV001526667.5 | |
Pathogenic (1) |
reviewed by expert panel
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Apr 10, 2022 | RCV002222031.3 |
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
(Apr 10, 2022)
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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: SCV002499510.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
The c.526C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 176 (p.(Gln176Ter)) of NM_000545.8. This variant, located in … (more)
The c.526C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 176 (p.(Gln176Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant also was identified in 15 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 18003757, internal lab contributors). This variant has a minor allele frequency of 0.000008856 in the gnomAD v2.1.1 European non-Finnish population and zero copies in other subpopulations, which is less than the ClinGen MDEP threshold for PM2_Supporting (less than or equal to 0.00002 and less than or equal to 1 copy in any other subpopulation) (PM2_Supporting). Additionally, this variant segregated with diabetes, with 5 informative meioses in 4 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.526C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PS4, PM2_Supporting, PP1_Strong, PP4_Moderate. (less)
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Pathogenic
(Apr 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Maturity onset diabetes mellitus in young
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV001656074.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Comment:
The c.526C>T (p.Gln176*, rs754728827) variant is located in exon 2 of the HNF1A gene. This single nucleotide substitution creates a premature stop codon at amino … (more)
The c.526C>T (p.Gln176*, rs754728827) variant is located in exon 2 of the HNF1A gene. This single nucleotide substitution creates a premature stop codon at amino acid position 176. This variant has been reported in an individual with a clinical diagnosis of MODY (PMID: 12107757), and variants that cause a loss of protein function are a well described cause of MODY. This is not a common variant in the general population (1 out of 245246 alleles in GnomAD). In summary, this variant is interpreted to be pathogenic. (less)
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Pathogenic
(Apr 30, 2019)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002067313.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.526C>T, which results in the creation of a premature stop codon at amino acid … (more)
DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.526C>T, which results in the creation of a premature stop codon at amino acid position 176, p.Gln176*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated HNF1A protein with potentially abnormal function. This pathogenic sequence change has previously been described in a patient with MODY (PMID: 12107757). (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: SCV001422862.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Gln176Ter variant in HNF1A has been reported in 1 Southern Chinese family with maturity-onset diabetes of the young type 3 (MODY3) and has been … (more)
The p.Gln176Ter variant in HNF1A has been reported in 1 Southern Chinese family with maturity-onset diabetes of the young type 3 (MODY3) and has been identified in 0.0008856% (1/112922) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754728827). This variant has also been reported in ClinVar (VariationID: 372380) as pathogenic by GeneDx. In vitro functional studies in HeLa cells transfected with the variant demonstrating null expression and transactivation activities similar to those of an empty vector alone provide some evidence that the p.Gln176Ter variant may impact protein function (PMID: 12107757). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 576, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in MODY3. In summary, this variant meets criteria to be classified as pathogenic for MODY3 in an autosomal dominant manner based on the prediction that it will cause loss of function of the HNF1A gene, low frequency of the variant in the general population, and in vitro functional studies. ACMG/AMP Criteria applied: PVS1, PM2, PS3_moderate (Richards 2015). (less)
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Pathogenic
(Aug 02, 2022)
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criteria provided, single submitter
Method: research
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Maturity-onset diabetes of the young type 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Geisinger Clinic, Geisinger Health System
Accession: SCV002562136.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
PVS1, PM2, PS4, PP1_Supporting, PP4_Moderate
Number of individuals with the variant: 1
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Pathogenic
(Mar 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002645179.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.Q176* pathogenic mutation (also known as c.526C>T), located in coding exon 2 of the HNF1A gene, results from a C to T substitution at … (more)
The p.Q176* pathogenic mutation (also known as c.526C>T), located in coding exon 2 of the HNF1A gene, results from a C to T substitution at nucleotide position 526. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This alteration was described in a family suspicious for MODY and functional studies showed a significant decrease in transactivation compared to wild-type (Xu JY et al. Diabetologia, 2002 May;45:744-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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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: SCV002605472.1
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 rs754728827 with MODY3. (less)
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Pathogenic
(Mar 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Maturity-onset diabetes of the young type 3
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV002762713.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
The HNF1A c.526C>T (p.Gln176Ter) nonsense variant results in the substitution of glutamine at amino acid position 176 with a stop codon. Loss of normal protein … (more)
The HNF1A c.526C>T (p.Gln176Ter) nonsense variant results in the substitution of glutamine at amino acid position 176 with a stop codon. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in a heterozygous state in at least six individuals with maturity onset diabetes of the young (Xu et al. 2002; Ma et al. 2020; Gaál et al. 2021). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000009 in the European (non-Finnish) population (version 2.1.1). In vitro studies in HeLa cells transfected with the c.526C>T variant demonstrated that the c.526C>T variant resulted in null expression and no detectable protein. Transactivation studies using a luciferase reporter assay showed 24.16% activity compared to wildtype, which was similar to an empty vector alone (Xu et al. 2002). Based on the available evidence, the c.526C>T (p.Gln176Ter) variant is classified as pathogenic for maturity onset diabetes of the young. (less)
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Pathogenic
(Oct 27, 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: SCV000490557.3
First in ClinVar: Jan 09, 2017 Last updated: Nov 25, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16496320, 25525159, 29625052, 36208030, 36451132, 35472491, 32238361, 34440499, 36257325, 36793123, 31166087, 12107757) (less)
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Pathogenic
(Sep 29, 2022)
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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: SCV004229330.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more)
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 12107757. (less)
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Pathogenic
(May 02, 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: SCV003442109.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 372380). This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the … (more)
ClinVar contains an entry for this variant (Variation ID: 372380). This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 12107757). This variant is present in population databases (rs754728827, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln176*) in the HNF1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1A are known to be pathogenic (PMID: 15928245, 18003757). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848499.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Gln176Ter variant in HNF1A has been reported in 1 Southern Chinese family with maturity-onset diabetes of the young (MODY; Xu 2002 PMID: 12107757) and … (more)
The p.Gln176Ter variant in HNF1A has been reported in 1 Southern Chinese family with maturity-onset diabetes of the young (MODY; Xu 2002 PMID: 12107757) and has been identified in 0.0009% (1/112922) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (VariationID: 372380). In vitro functional studies provide some evidence that the p.Gln176Ter variant may impact protein function (Xu 2002 PMID: 12107757). This nonsense variant leads to a premature termination codon at position 176, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in MODY. In summary, this variant meets criteria to be classified as pathogenic for MODY in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PM2, PS3_Supporting. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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protein loss of function
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Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV001656074.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. | Mirshahi UL | American journal of human genetics | 2022 | PMID: 36257325 |
Clinical and genetic heterogeneity of HNF4A/HNF1A mutations in a multicentre paediatric cohort with hyperinsulinaemic hypoglycaemia. | McGlacken-Byrne SM | European journal of endocrinology | 2022 | PMID: 35089870 |
A Comprehensive Analysis of Hungarian MODY Patients-Part I: Gene Panel Sequencing Reveals Pathogenic Mutations in HNF1A, HNF1B, HNF4A, ABCC8 and INS Genes. | Gaál Z | Life (Basel, Switzerland) | 2021 | PMID: 34440499 |
Missense Variants in PAX4 Are Associated with Early-Onset Diabetes in Chinese. | Gao A | Diabetes therapy : research, treatment and education of diabetes and related disorders | 2021 | PMID: 33216280 |
The ChinaMAP analytics of deep whole genome sequences in 10,588 individuals. | Cao Y | Cell research | 2020 | PMID: 32355288 |
New clinical screening strategy to distinguish HNF1A variant-induced diabetes from young early-onset type 2 diabetes in a Chinese population. | Ma Y | BMJ open diabetes research & care | 2020 | PMID: 32238361 |
Liver adenomatosis in patients with hepatocyte nuclear factor-1 alpha maturity onset diabetes of the young (HNF1A-MODY): Clinical, radiological and pathological characteristics in a French series. | Haddouche A | Journal of diabetes | 2020 | PMID: 31166087 |
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 |
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 |
Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients. | Xu JY | European journal of human genetics : EJHG | 2005 | PMID: 15657605 |
Mutations in the hepatocyte nuclear factor-1alpha gene in Chinese MODY families: prevalence and functional analysis. | Xu JY | Diabetologia | 2002 | PMID: 12107757 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5d825561-7155-4df0-9661-ceff7d791b78 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c304cf36-6aa8-475d-8d19-9ebcb10997e1 | - | - | - | - |
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Text-mined citations for rs754728827 ...
HelpRecord last updated Apr 20, 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.