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NM_000545.8(HNF1A):c.616T>A (p.Trp206Arg) AND Monogenic diabetes

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Apr 11, 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:
RCV000445512.5

Allele description [Variation Report for NM_000545.8(HNF1A):c.616T>A (p.Trp206Arg)]

NM_000545.8(HNF1A):c.616T>A (p.Trp206Arg)

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.616T>A (p.Trp206Arg)
Other names:
NM_000545.8(HNF1A):c.616T>A; p.Trp206Arg
HGVS:
  • NC_000012.12:g.120993609T>A
  • NG_011731.2:g.19864T>A
  • NM_000545.8:c.616T>AMANE SELECT
  • NM_001306179.2:c.616T>A
  • NP_000536.6:p.Trp206Arg
  • NP_001293108.2:p.Trp206Arg
  • LRG_522:g.19864T>A
  • NC_000012.11:g.121431412T>A
Protein change:
W206R
Links:
dbSNP: rs1057524898
NCBI 1000 Genomes Browser:
rs1057524898
Molecular consequence:
  • NM_000545.8:c.616T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306179.2:c.616T>A - 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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000537087Personalized Diabetes Medicine Program, University of Maryland School of Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Dec 4, 2015)
unknownresearch

PubMed (1)
[See all records that cite this PMID]

SCV002499518ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications v1 1)
Likely pathogenic
(Apr 11, 2022)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration
not providedunknownunknown1not providednot providednot providednot providedresearch

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Personalized Diabetes Medicine Program, University of Maryland School of Medicine, SCV000537087.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearch PubMed (1)

Description

ACMG Criteria: PM1 (HOX DNA binding domain), PM2, PP3

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot provided1not providednot providednot provided

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV002499518.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.616T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tryptophan to arginine at codon 206 (p.(Trp206Arg)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.899, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies) (PP4_Moderate; internal lab contributors). This variant 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). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.616T>A 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 September 30, 2021): PM1, PM2_Supporting, PP3, PP4_Moderate.

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

Last Updated: Jun 23, 2024