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NM_000545.8(HNF1A):c.517G>A (p.Val173Met) AND Monogenic diabetes

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 22, 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:
RCV003494035.2

Allele description [Variation Report for NM_000545.8(HNF1A):c.517G>A (p.Val173Met)]

NM_000545.8(HNF1A):c.517G>A (p.Val173Met)

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.517G>A (p.Val173Met)
Other names:
NM_001306179.2:c.517G>A
HGVS:
  • NC_000012.12:g.120989023G>A
  • NG_011731.2:g.15278G>A
  • NM_000545.8:c.517G>AMANE SELECT
  • NM_001306179.2:c.517G>A
  • NM_001406915.1:c.517G>A
  • NP_000536.5:p.Val173Met
  • NP_000536.6:p.Val173Met
  • NP_001293108.2:p.Val173Met
  • NP_001393844.1:p.Val173Met
  • LRG_522t1:c.517G>A
  • LRG_522:g.15278G>A
  • LRG_522p1:p.Val173Met
  • NC_000012.11:g.121426826G>A
  • NM_000545.5:c.517G>A
Protein change:
V173M
Molecular consequence:
  • NM_000545.8:c.517G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306179.2:c.517G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406915.1:c.517G>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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004242375ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications HNF1A V2.1.0)		Likely pathogenic
(Jan 22, 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, SCV004242375.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.517G>A variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to methionine at codon 173 (p.(Val173Met)) of NM_000545.8. This variant is located within the DNA binding domains (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, 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 0.84, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant segregated with diabetes, with at least ten informative meioses in one family (PP1_Strong; internal lab contributors). In summary, c.517G>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 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PP1_Strong.

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

Last Updated: Jun 23, 2024