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NM_000545.8(HNF1A):c.557T>C (p.Ile186Thr) AND Monogenic diabetes

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Apr 20, 2022
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:
RCV002250360.4

Allele description [Variation Report for NM_000545.8(HNF1A):c.557T>C (p.Ile186Thr)]

NM_000545.8(HNF1A):c.557T>C (p.Ile186Thr)

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.557T>C (p.Ile186Thr)
Other names:
NM_000545.8(HNF1A):c.557T>C; p.Ile186Thr
HGVS:
  • NC_000012.12:g.120993550T>C
  • NG_011731.2:g.19805T>C
  • NM_000545.8:c.557T>CMANE SELECT
  • NM_001306179.2:c.557T>C
  • NP_000536.6:p.Ile186Thr
  • NP_001293108.2:p.Ile186Thr
  • LRG_522:g.19805T>C
  • NC_000012.11:g.121431353T>C
Protein change:
I186T
Links:
dbSNP: rs587778396
NCBI 1000 Genomes Browser:
rs587778396
Molecular consequence:
  • NM_000545.8:c.557T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306179.2:c.557T>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
SCV002520645ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications v1 1)		Uncertain significance
(Apr 20, 2022) 		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, SCV002520645.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.557T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to threonine at codon 186 (p.(Ile186Thr)) of transcript NM_000545.8. This variant is located the HNF1A DNA binding domain, but outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 107-174 and 201-280); therefore, PM1_Supporting is not met. The frequency of the c.557T<C variant in gnomAD v2.1.1 is 0.00005278, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant has a REVEL score of 0.326, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (Internal lab contributors). In summary, c.557T>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, approved 9/30/2021): None.

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

Last Updated: Jun 23, 2024