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

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 29, 2023
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV003330315.2

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:
Monogenic diabetes
Identifiers:
MONDO: MONDO:0015967; MedGen: C3888631

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004037480ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications HNF4A V1.1.0)		Pathogenic
(Sep 29, 2023) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004037480.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.335G>A variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 112 (p.(Arg112Gln)) of NM_175914.5. This variant resides in an amino acid within the HNF4A DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.959, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 17 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 36257325, 25306193, 26552609, 18356407, internal lab contributors). At least one of these individuals had a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea-responsive) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 12 informative meioses in 11 families (PP1_Strong; PMID: 18356407, internal lab contributors). Another missense variant, c.334C>T p.Arg112Trp, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg112Gln (PM5_Supporting). In summary, c.335A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 8/11/2023): PS4, PP1_Strong, PM1, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting.

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

Last Updated: Sep 29, 2024