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NM_175914.5(HNF4A):c.331G>T (p.Glu111Ter) AND Monogenic diabetes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 5, 2024
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:
RCV003993722.1

Allele description [Variation Report for NM_175914.5(HNF4A):c.331G>T (p.Glu111Ter)]

NM_175914.5(HNF4A):c.331G>T (p.Glu111Ter)

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.331G>T (p.Glu111Ter)
Other names:
NM_175914.5:c.331G>T
HGVS:
  • NC_000020.11:g.44413705G>T
  • NG_009818.1:g.62905G>T
  • NM_000457.6:c.397G>T
  • NM_001030003.3:c.331G>T
  • NM_001030004.3:c.331G>T
  • NM_001258355.2:c.376G>T
  • NM_001287182.2:c.322G>T
  • NM_001287183.2:c.322G>T
  • NM_001287184.2:c.322G>T
  • NM_175914.5:c.331G>TMANE SELECT
  • NM_178849.3:c.397G>T
  • NM_178850.3:c.397G>T
  • NP_000448.3:p.Glu133Ter
  • NP_000448.3:p.Glu133Ter
  • NP_001025174.1:p.Glu111Ter
  • NP_001025175.1:p.Glu111Ter
  • NP_001245284.1:p.Glu126Ter
  • NP_001274111.1:p.Glu108Ter
  • NP_001274112.1:p.Glu108Ter
  • NP_001274112.1:p.Glu108Ter
  • NP_001274113.1:p.Glu108Ter
  • NP_787110.2:p.Glu111Ter
  • NP_787110.2:p.Glu111Ter
  • NP_849180.1:p.Glu133Ter
  • NP_849181.1:p.Glu133Ter
  • LRG_483t1:c.331G>T
  • LRG_483t2:c.397G>T
  • LRG_483t3:c.322G>T
  • LRG_483:g.62905G>T
  • LRG_483p1:p.Glu111Ter
  • LRG_483p2:p.Glu133Ter
  • LRG_483p3:p.Glu108Ter
  • NC_000020.10:g.43042345G>T
  • NM_000457.4:c.397G>T
  • NM_001287183.1:c.322G>T
  • NM_175914.4:c.331G>T
Protein change:
E108*
Molecular consequence:
  • NM_000457.6:c.397G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001030003.3:c.331G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001030004.3:c.331G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001258355.2:c.376G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001287182.2:c.322G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001287183.2:c.322G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001287184.2:c.322G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_175914.5:c.331G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_178849.3:c.397G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_178850.3:c.397G>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV004812229ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications HNF4A V2.0.0)		Pathogenic
(Apr 5, 2024) 		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, SCV004812229.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.331G>T variant in the hepatic nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 111 (p.(Glu111Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor). This variant segregated with diabetes with two informative meioses in this family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, c.331G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/23): PVS1, PP4, PM2_Supporting.

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

Last Updated: Apr 20, 2024