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.
ClinVar Genomic variation as it relates to human health
NM_175914.5(HNF4A):c.350C>T (p.Thr117Ile)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(11)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Benign/Likely benign
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_175914.5(HNF4A):c.350C>T (p.Thr117Ile)
Variation ID: 129240 Accession: VCV000129240.27
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 20q13.12 20: 44413724 (GRCh38) [ NCBI UCSC ] 20: 43042364 (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 May 17, 2014 Sep 29, 2024 Jan 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_175914.5:c.350C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_787110.2:p.Thr117Ile missense NM_000457.6:c.416C>T NP_000448.3:p.Thr139Ile missense NM_001030003.3:c.350C>T NP_001025174.1:p.Thr117Ile missense NM_001030004.3:c.350C>T NP_001025175.1:p.Thr117Ile missense NM_001258355.2:c.395C>T NP_001245284.1:p.Thr132Ile missense NM_001287182.2:c.341C>T NP_001274111.1:p.Thr114Ile missense NM_001287183.2:c.341C>T NP_001274112.1:p.Thr114Ile missense NM_001287184.2:c.341C>T NP_001274113.1:p.Thr114Ile missense NM_178849.3:c.416C>T NP_849180.1:p.Thr139Ile missense NM_178850.3:c.416C>T NP_849181.1:p.Thr139Ile missense NC_000020.11:g.44413724C>T NC_000020.10:g.43042364C>T NG_009818.1:g.62924C>T LRG_483:g.62924C>T LRG_483t1:c.350C>T LRG_483p1:p.Thr117Ile LRG_483t2:c.416C>T LRG_483p2:p.Thr139Ile LRG_483t3:c.341C>T LRG_483p3:p.Thr114Ile P41235:p.Thr139Ile - Protein change
- T114I, T117I, T139I, T132I
- Other names
-
p.T139I:ACT>ATT
- Canonical SPDI
- NC_000020.11:44413723:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.02396 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.02376
1000 Genomes Project 0.02396
Trans-Omics for Precision Medicine (TOPMed) 0.02447
The Genome Aggregation Database (gnomAD) 0.02469
1000 Genomes Project 30x 0.02530
The Genome Aggregation Database (gnomAD), exomes 0.03077
Exome Aggregation Consortium (ExAC) 0.03200
- 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. |
|||
| HNF4A | - | - |
GRCh38 GRCh37 |
637 | 650 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 28, 2016 | RCV000117238.18 | |
| Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000280314.8 | |
| Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000337755.8 | |
| Benign (1) |
criteria provided, single submitter
|
Jan 25, 2019 | RCV000445529.7 | |
| Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV001521057.11 | |
| Benign (1) |
criteria provided, single submitter
|
- | RCV002226673.4 | |
| Benign (1) |
criteria provided, single submitter
|
Jul 16, 2015 | RCV002453432.4 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000316593.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity-onset diabetes of the young type 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000433893.3
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
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hyperinsulinism
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000433892.3
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Benign
(Jan 25, 2019)
|
criteria provided, single submitter
Method: research
|
Monogenic diabetes
Affected status: unknown
Allele origin:
unknown
|
Personalized Diabetes Medicine Program, University of Maryland School of Medicine
Accession: SCV000537113.3
First in ClinVar: Mar 14, 2017 Last updated: Jun 13, 2020 |
Comment:
ACMG criteria: BA1 (Overall MAF in gnomAD 3%, 4.1% in European Finnish and 4.6% Latino), BS2 (549 cases and 492 controls in T2DM)= Benign (Note: … (more)
ACMG criteria: BA1 (Overall MAF in gnomAD 3%, 4.1% in European Finnish and 4.6% Latino), BS2 (549 cases and 492 controls in T2DM)= Benign (Note: ClinVar=benign with 2 stars, Chicago and GeneDx call it benign . BP4 not being used because REVEL 0.426, BP6 no longer applied) (less)
Number of individuals with the variant: 21
Zygosity: Homozygote, Single Heterozygote
|
|
|
Benign
(Apr 23, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000168829.10
First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016 |
Comment:
This variant is associated with the following publications: (PMID: 26981542, 29632382, 12669197, 20878384, 22995991, 15728204, 24503134, 24097065, 20981092, 10983627, 27884173, 27346685, 28008009, 26551672, 26105150, 24448600, … (more)
This variant is associated with the following publications: (PMID: 26981542, 29632382, 12669197, 20878384, 22995991, 15728204, 24503134, 24097065, 20981092, 10983627, 27884173, 27346685, 28008009, 26551672, 26105150, 24448600, 30297969, 25361053, 26503572) (less)
|
|
|
Benign
(Mar 05, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
AllHighlyPenetrant
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000151411.1
First in ClinVar: May 17, 2014 Last updated: May 17, 2014 |
|
|
|
Likely benign
(Mar 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539310.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 309/13006=2.3% (less)
Method: Genome/Exome Filtration
|
|
|
Benign
(-)
|
criteria provided, single submitter
Method: research
|
Type 2 diabetes mellitus
Affected status: yes
Allele origin:
somatic
|
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002505502.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Comment:
rs1800961, a loss-of-function mutation in HNF4A is associated with poor insulin secretion in response to hyperglycemia. These are associated with MODY1. Patients initially respond well … (more)
rs1800961, a loss-of-function mutation in HNF4A is associated with poor insulin secretion in response to hyperglycemia. These are associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. This variant is also associated with increased risk of T2DM and periodontitis. (less)
|
|
|
Benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001730311.4
First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024 |
|
|
|
Benign
(Jul 16, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002614616.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Likely benign
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005208732.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
|
|
| click to load more click to collapse | |||||
Comment:
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
ACMG criteria: BA1 (Overall MAF in gnomAD 3%, 4.1% in European Finnish and 4.6% Latino), BS2 (549 cases and 492 controls in T2DM)= Benign (Note: ClinVar=benign with 2 stars, Chicago and GeneDx call it benign . BP4 not being used because REVEL 0.426, BP6 no longer applied)
Comment:
This variant is associated with the following publications: (PMID: 26981542, 29632382, 12669197, 20878384, 22995991, 15728204, 24503134, 24097065, 20981092, 10983627, 27884173, 27346685, 28008009, 26551672, 26105150, 24448600, 30297969, 25361053, 26503572)
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 309/13006=2.3%
Comment:
rs1800961, a loss-of-function mutation in HNF4A is associated with poor insulin secretion in response to hyperglycemia. These are associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. This variant is also associated with increased risk of T2DM and periodontitis.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This variant 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 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
ACMG criteria: BA1 (Overall MAF in gnomAD 3%, 4.1% in European Finnish and 4.6% Latino), BS2 (549 cases and 492 controls in T2DM)= Benign (Note: ClinVar=benign with 2 stars, Chicago and GeneDx call it benign . BP4 not being used because REVEL 0.426, BP6 no longer applied)
Comment:
This variant is associated with the following publications: (PMID: 26981542, 29632382, 12669197, 20878384, 22995991, 15728204, 24503134, 24097065, 20981092, 10983627, 27884173, 27346685, 28008009, 26551672, 26105150, 24448600, 30297969, 25361053, 26503572)
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 309/13006=2.3%
Comment:
rs1800961, a loss-of-function mutation in HNF4A is associated with poor insulin secretion in response to hyperglycemia. These are associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. This variant is also associated with increased risk of T2DM and periodontitis.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Polymorphisms in Genes of Lipid Metabolism Are Associated with Type 2 Diabetes Mellitus and Periodontitis, as Comorbidities, and with the Subjects' Periodontal, Glycemic, and Lipid Profiles. | Nicchio IG | Journal of diabetes research | 2021 | PMID: 34805411 |
| Identification of HNF4A Mutation p.T130I and HNF1A Mutations p.I27L and p.S487N in a Han Chinese Family with Early-Onset Maternally Inherited Type 2 Diabetes. | Yang Y | Journal of diabetes research | 2016 | PMID: 26981542 |
| Novel genetic variations and haplotypes of hepatocyte nuclear factor 4alpha (HNF4A) found in Japanese type II diabetic patients. | Fukushima-Uesaka H | Drug metabolism and pharmacokinetics | 2006 | PMID: 16946562 |
| T130I mutation in HNF-4alpha gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects. | Zhu Q | Diabetologia | 2003 | PMID: 12669197 |
| Mutations in the hepatocyte nuclear factor-4alpha gene in Japanese with non-insulin-dependent diabetes: a nucleotide substitution in the polypyrimidine tract of intron 1b. | Sakurai K | Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | 2000 | PMID: 10983627 |
| type2diabetesgenetics.org | - | - | - | - |
Text-mined citations for rs1800961 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jan 13, 2025
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.