NM_175914.5(HNF4A):c.439G>A (p.Val147Ile) AND Type 2 diabetes mellitus

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 18, 2016
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000490471.13

Allele description [Variation Report for NM_175914.5(HNF4A):c.439G>A (p.Val147Ile)]

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

Gene:

HNF4A:hepatocyte nuclear factor 4 alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q13.12

Genomic location:

Preferred name:

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

HGVS:

NC_000020.11:g.44414519G>A
NG_009818.1:g.63719G>A
NM_000457.6:c.505G>A
NM_001030003.3:c.439G>A
NM_001030004.3:c.439G>A
NM_001258355.2:c.484G>A
NM_001287182.2:c.430G>A
NM_001287183.2:c.430G>A
NM_001287184.2:c.430G>A
NM_175914.5:c.439G>AMANE SELECT
NM_178849.3:c.505G>A
NM_178850.3:c.505G>A
NP_000448.3:p.Val169Ile
NP_000448.3:p.Val169Ile
NP_001025174.1:p.Val147Ile
NP_001025175.1:p.Val147Ile
NP_001245284.1:p.Val162Ile
NP_001274111.1:p.Val144Ile
NP_001274112.1:p.Val144Ile
NP_001274113.1:p.Val144Ile
NP_787110.2:p.Val147Ile
NP_787110.2:p.Val147Ile
NP_849180.1:p.Val169Ile
NP_849181.1:p.Val169Ile
LRG_483t1:c.439G>A
LRG_483t2:c.505G>A
LRG_483:g.63719G>A
LRG_483p1:p.Val147Ile
LRG_483p2:p.Val169Ile
NC_000020.10:g.43043159G>A
NM_000457.3:c.505G>A
NM_000457.4:c.505G>A
NM_175914.3:c.439G>A
NM_175914.4:c.439G>A
p.VAL169ILE

Protein change:

V144I

Links:

dbSNP: rs142204928

NCBI 1000 Genomes Browser:

rs142204928

Molecular consequence:

NM_000457.6:c.505G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001030003.3:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001030004.3:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258355.2:c.484G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287182.2:c.430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287183.2:c.430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287184.2:c.430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_175914.5:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_178849.3:c.505G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_178850.3:c.505G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Type 2 diabetes mellitus
Synonyms:: DIABETES MELLITUS, TYPE 2, PROTECTION AGAINST; Type II diabetes mellitus; Diabetes mellitus, noninsulin-dependent, late onset
Identifiers:: MONDO: MONDO:0005148; MeSH: D003924; MedGen: C0011860; OMIM: 125853; Human Phenotype Ontology: HP:0005978

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000267357	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 18, 2016)	germline	reference population	PubMed (2) [See all records that cite these PMIDs] 15281001, 25741868
SCV001435151	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign	germline	research	PubMed (3) [See all records that cite these PMIDs] 15281001, 24097065, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000267357

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 18, 2016)

germline

reference population

PubMed (2)
[See all records that cite these PMIDs]

SCV001435151

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign

germline

research

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
East Asian	germline	unknown	1	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

Triple genetic variation in the HNF-4alpha gene is associated with early-onset type 2 diabetes mellitus in a philippino family.

Gragnoli C, Menzinger Von Preussenthal G, Habener JF.

Metabolism. 2004 Aug;53(8):959-63.

PubMed [citation]

PMID:: 15281001

Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes.

Flannick J, Beer NL, Bick AG, Agarwala V, Molnes J, Gupta N, Burtt NP, Florez JC, Meigs JB, Taylor H, Lyssenko V, Irgens H, Fox E, Burslem F, Johansson S, Brosnan MJ, Trimmer JK, Newton-Cheh C, Tuomi T, Molven A, Wilson JG, O'Donnell CJ, et al.

Nat Genet. 2013 Nov;45(11):1380-5. doi: 10.1038/ng.2794. Epub 2013 Oct 6.

PubMed [citation]

PMID:: 24097065
PMCID:: PMC4051627

See all PubMed Citations (3)

Details of each submission

From Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267357.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	1	not provided	not provided	reference population	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001435151.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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