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NM_175914.5(HNF4A):c.48C>G (p.Tyr16Ter) AND Maturity-onset diabetes of the young type 1

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
May 4, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001730179.2

Allele description [Variation Report for NM_175914.5(HNF4A):c.48C>G (p.Tyr16Ter)]

NM_175914.5(HNF4A):c.48C>G (p.Tyr16Ter)

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.48C>G (p.Tyr16Ter)
Other names:
NM_175914.5(HNF4A):c.48C>G; p.Tyr16Ter
HGVS:
  • NC_000020.11:g.44355852C>G
  • NG_009818.1:g.5052C>G
  • NM_001030003.3:c.48C>G
  • NM_001030004.3:c.48C>G
  • NM_001287182.2:c.-184C>G
  • NM_001287183.2:c.-184C>G
  • NM_001287184.2:c.-184C>G
  • NM_175914.5:c.48C>GMANE SELECT
  • NP_001025174.1:p.Tyr16Ter
  • NP_001025175.1:p.Tyr16Ter
  • NP_787110.2:p.Tyr16Ter
  • LRG_483:g.5052C>G
  • NC_000020.10:g.42984492C>G
Protein change:
Y16*
Links:
dbSNP: rs2146127862
NCBI 1000 Genomes Browser:
rs2146127862
Molecular consequence:
  • NM_001287182.2:c.-184C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001287183.2:c.-184C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001287184.2:c.-184C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001030003.3:c.48C>G - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001030004.3:c.48C>G - nonsense - [Sequence Ontology: SO:0001587]
  • NM_175914.5:c.48C>G - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

Name:
Maturity-onset diabetes of the young type 1
Synonyms:
MILD JUVENILE DIABETES MELLITUS; MODY type 1; Diabetes mellitus MODY type 1; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007452; MedGen: C1852093; Orphanet: 552; OMIM: 125850

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001977598Exeter Molecular Genetics Laboratory
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Oct 5, 2021) 		inheritedclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002516549Mendelics
criteria provided, single submitter

(Mendelics Assertion Criteria 2019)		Pathogenic
(May 4, 2022) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedinheritedyes81not providednot providedyesclinical testing

Citations

PubMed

Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations.

Kapoor RR, Locke J, Colclough K, Wales J, Conn JJ, Hattersley AT, Ellard S, Hussain K.

Diabetes. 2008 Jun;57(6):1659-63. doi: 10.2337/db07-1657. Epub 2008 Feb 11.

PubMed [citation]
PMID:
18268044

Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.

Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT.

PLoS Med. 2007 Apr;4(4):e118.

PubMed [citation]
PMID:
17407387
PMCID:
PMC1845156
See all PubMed Citations (3)

Details of each submission

From Exeter Molecular Genetics Laboratory, SCV001977598.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided8not providedyesclinical testing PubMed (3)

Description

The c.48C>G variant in the HNF4 homeobox A gene, HNF4A, Results in the substitution of a tyrosine amino acid to a termination codon (p.Tyr16Ter) in exon 1 of the pancreatic specific HNF4A isoform NM_175914.5. This variant is predicted to generate an mRNA with a premature termination codon that would undergo nonsense mediated decay resulting in absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Very Strong; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified by our laboratory in an individual with clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate). This variant also segregated with diabetes in this family with 7 informative meioses (PP1_Strong). In summary, c.48C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied: PVS1_Very Strong, PP1_Strong, PP4_Moderate, PM2_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot provided8not provided1not provided

From Mendelics, SCV002516549.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 14, 2024