ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.676_678del (p.Lys226del)

dbSNP: rs1555211927
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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 RCV002222036 SCV002499520 uncertain significance Monogenic diabetes 2022-04-11 reviewed by expert panel curation The c.676_678del variant in the HNF1 homeobox A gene, HNF1A, is a three base pair deletion resulting in the in-frame deletion of one amino acid at codon 226 (p.(Lys226del)) within exon 3 of NM_000545.8. 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). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). The c.676_678del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). Lastly, this variant was identified in an individual with a clinical history specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.676_678del 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 (specification version 1.1, approved 9/30/21): PM1_Supporting, PM2_Supporting, PM4_Supporting, PP4.
Genetic Services Laboratory, University of Chicago RCV000500461 SCV000595141 likely pathogenic Maturity-onset diabetes of the young type 3 2017-03-27 criteria provided, single submitter clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002463450 SCV002604990 likely benign 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 rs1555211927 with MODY3.

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