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NM_175914.5(HNF4A):c.337G>C (p.Asp113His) AND Monogenic diabetes

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 27, 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:
RCV003228708.2

Allele description [Variation Report for NM_175914.5(HNF4A):c.337G>C (p.Asp113His)]

NM_175914.5(HNF4A):c.337G>C (p.Asp113His)

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.337G>C (p.Asp113His)
Other names:
NM_175914.5:c.337G>C
HGVS:
  • NC_000020.11:g.44413711G>C
  • NG_009818.1:g.62911G>C
  • NM_000457.6:c.403G>C
  • NM_001030003.3:c.337G>C
  • NM_001030004.3:c.337G>C
  • NM_001258355.2:c.382G>C
  • NM_001287182.2:c.328G>C
  • NM_001287183.2:c.328G>C
  • NM_001287184.2:c.328G>C
  • NM_175914.5:c.337G>CMANE SELECT
  • NM_178849.3:c.403G>C
  • NM_178850.3:c.403G>C
  • NP_000448.3:p.Asp135His
  • NP_000448.3:p.Asp135His
  • NP_001025174.1:p.Asp113His
  • NP_001025175.1:p.Asp113His
  • NP_001245284.1:p.Asp128His
  • NP_001274111.1:p.Asp110His
  • NP_001274112.1:p.Asp110His
  • NP_001274112.1:p.Asp110His
  • NP_001274113.1:p.Asp110His
  • NP_787110.2:p.Asp113His
  • NP_787110.2:p.Asp113His
  • NP_849180.1:p.Asp135His
  • NP_849181.1:p.Asp135His
  • LRG_483t1:c.337G>C
  • LRG_483t2:c.403G>C
  • LRG_483t3:c.328G>C
  • LRG_483:g.62911G>C
  • LRG_483p1:p.Asp113His
  • LRG_483p2:p.Asp135His
  • LRG_483p3:p.Asp110His
  • NC_000020.10:g.43042351G>C
  • NM_000457.4:c.403G>C
  • NM_001287183.1:c.328G>C
  • NM_175914.4:c.337G>C
Protein change:
D110H
Molecular consequence:
  • NM_000457.6:c.403G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001030003.3:c.337G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001030004.3:c.337G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258355.2:c.382G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287182.2:c.328G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287183.2:c.328G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287184.2:c.328G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_175914.5:c.337G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_178849.3:c.403G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_178850.3:c.403G>C - 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
SCV003925534ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(MDEP HNF4A Specificiations 1.0.0)		Uncertain significance
(Mar 27, 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, SCV003925534.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.337G>C variant in the hepatocyte nuclear factor -4 alpha gene, HNF4A, causes an amino acid change of asparagine to a histidine at codon 113 (p.(Asp113His)) of NM_175914.5. Functional studies have demonstrated the p. Asp113His protein has DNA binding below 40% of wild type indicating that this variant impacts protein function (PS3_Supporting; PMID: 15233628). Additionally, this variant resides in an amino acid within the HNF4A DNA binding domain that directly binds DNA, which is necessary for homodimer formation and defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). Based on its REVEL score of 0.959, which is greater than the MDEP VCEP threshold of 0.70, this variant is predicted to be deleterious by computational evidence (PP3). The variant was found in an individual with diabetes who was a compound heterozygote for this variant and p.Asp113Tyr; however, the MODY probability calculator score was <50% and there was evidence of an autoimmune etiology, and PP4 could not be applied (PMID: 11232004). The p.Asp113Tyr variant is a VUS; therefore, PM5 could not be applied. In summary, c.337G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1,0, approved 11/16/2022): PS3_Supporting, PM1_Moderate, PM2_Supporting, PP3.

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

Last Updated: Jun 23, 2024