VCV000036353.33 - ClinVar

NM_175914.5(HNF4A):c.439G>A (p.Val147Ile)

Germline

Classification

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.

(13)

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(1); Benign(5); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_175914.5(HNF4A):c.439G>A (p.Val147Ile)

Variation ID: 36353 Accession: VCV000036353.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.12 20: 44414519 (GRCh38) [ NCBI UCSC ] 20: 43043159 (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	Oct 20, 2024	Jan 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_175914.5:c.439G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_787110.2:p.Val147Ile	missense
NM_000457.6:c.505G>A	NP_000448.3:p.Val169Ile	missense
NM_001030003.3:c.439G>A	NP_001025174.1:p.Val147Ile	missense
NM_001030004.3:c.439G>A	NP_001025175.1:p.Val147Ile	missense
NM_001258355.2:c.484G>A	NP_001245284.1:p.Val162Ile	missense
NM_001287182.2:c.430G>A	NP_001274111.1:p.Val144Ile	missense
NM_001287183.2:c.430G>A	NP_001274112.1:p.Val144Ile	missense
NM_001287184.2:c.430G>A	NP_001274113.1:p.Val144Ile	missense
NM_178849.3:c.505G>A	NP_849180.1:p.Val169Ile	missense
NM_178850.3:c.505G>A	NP_849181.1:p.Val169Ile	missense
NC_000020.11:g.44414519G>A
NC_000020.10:g.43043159G>A
NG_009818.1:g.63719G>A
LRG_483:g.63719G>A
LRG_483t1:c.439G>A	LRG_483p1:p.Val147Ile
LRG_483t2:c.505G>A	LRG_483p2:p.Val169Ile

... more HGVS ... less HGVS

Protein change

V147I, V169I, V144I, V162I

Other names

Canonical SPDI

NC_000020.11:44414518:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00599 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00037

The Genome Aggregation Database (gnomAD), exomes 0.00201

Exome Aggregation Consortium (ExAC) 0.00234

1000 Genomes Project 30x 0.00500

1000 Genomes Project 0.00599

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

The Genome Aggregation Database (gnomAD) 0.00025

Links

ClinGen: CA213951 dbSNP: rs142204928 VarSome

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
Gene	OMIM	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	594	607

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.
Maturity-onset diabetes of the young type 1	Likely benign (2)	criteria provided, single submitter	Apr 27, 2017	RCV000030023.14
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Jan 18, 2024	RCV000117239.32
Familial hyperinsulinism	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000340715.13
Type 2 diabetes mellitus	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Mar 18, 2016	RCV000490471.13
not specified	Benign (3)	criteria provided, single submitter	Nov 14, 2016	RCV000516787.16
Maturity onset diabetes mellitus in young	Benign (1)	criteria provided, single submitter	Apr 27, 2021	RCV002326694.9

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.
Uncertain significance (Mar 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: reference population	Type 2 diabetes mellitus Affected status: unknown Allele origin: germline	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center Accession: SCV000267357.1 First in ClinVar: May 25, 2017 Last updated: May 25, 2017	Publications: PubMed (1) PubMed: 15281001 Number of individuals with the variant: 1 Age: 40-69 years Ethnicity/Population group: East Asian Geographic origin: South Korean
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Maturity-onset diabetes of the young type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000433897.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 15281001 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 (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial hyperinsulinism Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000433896.3 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 (Apr 27, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Maturity onset diabetes mellitus in young Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002628803.2 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)
Benign (Nov 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004183910.9 First in ClinVar: Dec 24, 2023 Last updated: Oct 20, 2024	Comment: HNF4A: BP4, BS1, BS2 Number of individuals with the variant: 1
Benign (Nov 14, 2016)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000613656.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (4) PubMed: 25041077‚ 27420379‚ 27080136‚ 15281001
Benign (Feb 13, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001753226.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: This variant is associated with the following publications: (PMID: 32621647, 31216263, 25041077, 27080136, 27535533, 27810688, 15281001, 24097065)
Benign (Jan 18, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002461206.3 First in ClinVar: Apr 08, 2022 Last updated: Feb 14, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Type 2 diabetes mellitus (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435151.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (2) PubMed: 15281001‚ 24097065 Comment: The heterozygous p.Val147Ile variant in HNF4A has been identified in 3 Philippino siblings from 1 family with maturity onset diabetes of the young and 2 … (more) The heterozygous p.Val147Ile variant in HNF4A has been identified in 3 Philippino siblings from 1 family with maturity onset diabetes of the young and 2 individuals without diabetes mellitus (PMID: 15281001, 24097065), but has also been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Please note that individuals in ExAC may have type II diabetes. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant diabetes mellitus type 2. (less)
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: SCV002033998.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Benign (May 02, 2019)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002067856.3 First in ClinVar: Jan 29, 2022 Last updated: Dec 11, 2022
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: SCV002036591.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
not provided (Oct 02, 2015)	no classification provided Method: clinical testing	Maturity-onset diabetes of the young, type 1 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052678.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 29, 2015
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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:

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.

Comment:

The heterozygous p.Val147Ile variant in HNF4A has been identified in 3 Philippino siblings from 1 family with maturity onset diabetes of the young and 2 individuals without diabetes mellitus (PMID: 15281001, 24097065), but has also been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Please note that individuals in ExAC may have type II diabetes. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant diabetes mellitus type 2.

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). 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A preliminary study to evaluate the strategy of combining clinical criteria and next generation sequencing (NGS) for the identification of monogenic diabetes among multi-ethnic Asians.	Ang SF	Diabetes research and clinical practice	2016	PMID: 27420379
Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes.	Flannick J	Nature reviews. Endocrinology	2016	PMID: 27080136
Maturity onset diabetes of the young in India - a distinctive mutation pattern identified through targeted next-generation sequencing.	Chapla A	Clinical endocrinology	2015	PMID: 25041077
Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes.	Flannick J	Nature genetics	2013	PMID: 24097065
Triple genetic variation in the HNF-4alpha gene is associated with early-onset type 2 diabetes mellitus in a philippino family.	Gragnoli C	Metabolism: clinical and experimental	2004	PMID: 15281001

Text-mined citations for rs142204928 ...

These 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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_175914.5(HNF4A):c.439G>A (p.Val147Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs142204928 ...