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NM_175914.5(HNF4A):c.335G>A (p.Arg112Gln) AND Maturity onset diabetes mellitus in young

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 29, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV003317241.2

Allele description [Variation Report for NM_175914.5(HNF4A):c.335G>A (p.Arg112Gln)]

NM_175914.5(HNF4A):c.335G>A (p.Arg112Gln)

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.335G>A (p.Arg112Gln)
Other names:
NM_175914.5(HNF4A):c.335G>A; p.Arg112Gln
HGVS:
  • NC_000020.11:g.44413709G>A
  • NG_009818.1:g.62909G>A
  • NM_000457.6:c.401G>A
  • NM_001030003.3:c.335G>A
  • NM_001030004.3:c.335G>A
  • NM_001258355.2:c.380G>A
  • NM_001287182.2:c.326G>A
  • NM_001287183.2:c.326G>A
  • NM_001287184.2:c.326G>A
  • NM_175914.5:c.335G>AMANE SELECT
  • NM_178849.3:c.401G>A
  • NM_178850.3:c.401G>A
  • NP_000448.3:p.Arg134Gln
  • NP_000448.3:p.Arg134Gln
  • NP_001025174.1:p.Arg112Gln
  • NP_001025175.1:p.Arg112Gln
  • NP_001245284.1:p.Arg127Gln
  • NP_001274111.1:p.Arg109Gln
  • NP_001274112.1:p.Arg109Gln
  • NP_001274113.1:p.Arg109Gln
  • NP_787110.2:p.Arg112Gln
  • NP_849180.1:p.Arg134Gln
  • NP_849181.1:p.Arg134Gln
  • LRG_483t1:c.335G>A
  • LRG_483t2:c.401G>A
  • LRG_483:g.62909G>A
  • LRG_483p2:p.Arg134Gln
  • NC_000020.10:g.43042349G>A
  • NM_000457.4:c.401G>A
  • NM_175914.3:c.335G>A
  • NM_175914.4:c.335G>A
Protein change:
R109Q
Links:
dbSNP: rs1085307913
NCBI 1000 Genomes Browser:
rs1085307913
Molecular consequence:
  • NM_000457.6:c.401G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001030003.3:c.335G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001030004.3:c.335G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258355.2:c.380G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287182.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287183.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287184.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_175914.5:c.335G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_178849.3:c.401G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_178850.3:c.401G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Maturity onset diabetes mellitus in young (MODY)
Synonyms:
Mason type diabetes
Identifiers:
MONDO: MONDO:0018911; MedGen: C0342276; Orphanet: 552; OMIM: 606391; Human Phenotype Ontology: HP:0004904

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004020406Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jun 29, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

The diabetic phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during fetal development.

Harries LW, Locke JM, Shields B, Hanley NA, Hanley KP, Steele A, Njølstad PR, Ellard S, Hattersley AT.

Diabetes. 2008 Jun;57(6):1745-52. doi: 10.2337/db07-1742. Epub 2008 Mar 20.

PubMed [citation]
PMID:
18356407

Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach.

Alkorta-Aranburu G, Carmody D, Cheng YW, Nelakuditi V, Ma L, Dickens JT, Das S, Greeley SAW, Del Gaudio D.

Mol Genet Metab. 2014 Dec;113(4):315-320. doi: 10.1016/j.ymgme.2014.09.007. Epub 2014 Sep 28.

PubMed [citation]
PMID:
25306193
PMCID:
PMC4756642
See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020406.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: HNF4A c.335G>A (p.Arg112Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250614 control chromosomes. c.335G>A has been reported in the literature in individuals affected with Maturity Onset Diabetes of the Young 1 (MODY1)/Neonatal Diabetes Mellitus (e.g. Harries_2008, Alkorta-Aranburu_2014, Hamilton_2014, Sztromwasser_2020, Colcough_2022, Dusatkova_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25306193, 34789499, 24285859, 18356407, 31825128). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024