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NM_175914.5(HNF4A):c.125G>T (p.Gly42Val) AND Monogenic diabetes

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Aug 18, 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:
RCV003326071.3

Allele description [Variation Report for NM_175914.5(HNF4A):c.125G>T (p.Gly42Val)]

NM_175914.5(HNF4A):c.125G>T (p.Gly42Val)

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.125G>T (p.Gly42Val)
Other names:
NM_175914.5:c.125G>T
HGVS:
  • NC_000020.11:g.44406133G>T
  • NG_009818.1:g.55333G>T
  • NM_000457.6:c.191G>T
  • NM_001030003.3:c.125G>T
  • NM_001030004.3:c.125G>T
  • NM_001258355.2:c.170G>T
  • NM_001287182.2:c.116G>T
  • NM_001287183.2:c.116G>T
  • NM_001287184.2:c.116G>T
  • NM_175914.5:c.125G>TMANE SELECT
  • NM_178849.3:c.191G>T
  • NM_178850.3:c.191G>T
  • NP_000448.3:p.Gly64Val
  • NP_000448.3:p.Gly64Val
  • NP_001025174.1:p.Gly42Val
  • NP_001025175.1:p.Gly42Val
  • NP_001245284.1:p.Gly57Val
  • NP_001274111.1:p.Gly39Val
  • NP_001274112.1:p.Gly39Val
  • NP_001274112.1:p.Gly39Val
  • NP_001274113.1:p.Gly39Val
  • NP_787110.2:p.Gly42Val
  • NP_787110.2:p.Gly42Val
  • NP_849180.1:p.Gly64Val
  • NP_849181.1:p.Gly64Val
  • LRG_483t1:c.125G>T
  • LRG_483t2:c.191G>T
  • LRG_483t3:c.116G>T
  • LRG_483:g.55333G>T
  • LRG_483p1:p.Gly42Val
  • LRG_483p2:p.Gly64Val
  • LRG_483p3:p.Gly39Val
  • NC_000020.10:g.43034773G>T
  • NM_000457.4:c.191G>T
  • NM_001287183.1:c.116G>T
  • NM_175914.4:c.125G>T
Protein change:
G39V
Molecular consequence:
  • NM_000457.6:c.191G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001030003.3:c.125G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001030004.3:c.125G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258355.2:c.170G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287182.2:c.116G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287183.2:c.116G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287184.2:c.116G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_175914.5:c.125G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_178849.3:c.191G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_178850.3:c.191G>T - 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
SCV004032067ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications HNF4A V1.1.0)		Likely pathogenic
(Aug 18, 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, SCV004032067.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.125G>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glycine to valine at codon 42 (p.(Gly42Val)) of NM_175914.5. This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and responsive to sulfonylurea) (PP4_Moderate; internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the DNA binding domain (codons 37-113 of HNF4A), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.124G>A p.Gly42Arg, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.125G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0 approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting.

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

Last Updated: Jun 23, 2024