ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.494G>A (p.Trp165Ter)

dbSNP: rs1555211436
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV002259985 SCV002540112 pathogenic Monogenic diabetes 2022-06-10 reviewed by expert panel curation The c.494G>A variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 165 (p.(Trp165Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Furthermore, this variant segregated with diabetes, with three informative meioses, in one family with MODY (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability estimated between 39-59% based on available clinical information, sulfonylurea-sensitive, and negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.494G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting, PP1_Moderate, PP4.
Athena Diagnostics RCV000516743 SCV000613616 likely pathogenic not provided 2017-04-17 criteria provided, single submitter clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002319514 SCV002604966 pathogenic Maturity onset diabetes mellitus in young criteria provided, single submitter research Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs1555211436 with MODY3.

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