ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.663GAA[1] (p.Lys222del)

dbSNP: rs193922599
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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 RCV002222010 SCV002499519 likely pathogenic Monogenic diabetes 2022-04-11 reviewed by expert panel curation The c.666_668del variant in the HNF1 homeoboxA gene, HNF1A, results in a deletion of Lysine at codon 222 of NM_000545.6 (PM4_Supporting). Functional in vitro studies demonstrated that cells with this variant showed severely impaired transactivation activity and DNA binding (significantly below 40%). Furthermore, cells with this variant showed low protein expression levels and impaired nuclear targeting with elevated immunofluorescence signal in the cytoplasm compared to WT HNF1A (PS3; Janne Molnes, personal communication). 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). This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea-responsiveness in both and negative antibodies in one) (PP4_Moderate; PMID: 27913849, internal lab contributor). This variant segregated with disease with three informative meioses in a single family with MODY (PP1; internal lab contributor). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.666_668del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 9/30/2021): PS3, PM1, PP4_Moderate, PM2_Supporting, PM4_Supporting, PP1.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030506 SCV000053177 likely pathogenic Maturity-onset diabetes of the young type 3 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002463434 SCV002604988 uncertain significance 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 rs193922599with MODY3.

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