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NM_000545.8(HNF1A):c.670C>T (p.Pro224Ser) AND Monogenic diabetes

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 30, 2021
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:
RCV001810406.4

Allele description [Variation Report for NM_000545.8(HNF1A):c.670C>T (p.Pro224Ser)]

NM_000545.8(HNF1A):c.670C>T (p.Pro224Ser)

Gene:
HNF1A:HNF1 homeobox A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q24.31
Genomic location:
Preferred name:
NM_000545.8(HNF1A):c.670C>T (p.Pro224Ser)
Other names:
NM_000545.6(HNF1A):c.670C>T
HGVS:
  • NC_000012.12:g.120993663C>T
  • NG_011731.2:g.19918C>T
  • NM_000545.8:c.670C>TMANE SELECT
  • NM_001306179.2:c.670C>T
  • NP_000536.6:p.Pro224Ser
  • NP_001293108.2:p.Pro224Ser
  • LRG_522t1:c.670C>T
  • LRG_522:g.19918C>T
  • NC_000012.11:g.121431466C>T
  • NM_000545.5:c.670C>T
Protein change:
P224S
Links:
dbSNP: rs193922600
NCBI 1000 Genomes Browser:
rs193922600
Molecular consequence:
  • NM_000545.8:c.670C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306179.2:c.670C>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
SCV002059973ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications v1 1)		Likely pathogenic
(Dec 30, 2021) 		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, SCV002059973.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.670C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 224 (p.(Pro224Ser)) of NM_000545.8. This variant segregated with diabetes, with four informative meioses in three families with MODY (PP1_Strong; PMID: 15031772, internal lab contributors) and this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.944, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). Additionally, this variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Lastly, the c.670C>T variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.670C>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, approved June 4, 2021): PP1_Strong, PP3, PP4_Moderate, PM1_Supporting, PM2_Supporting

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

Last Updated: Jun 23, 2024