ClinVar Miner

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

dbSNP: rs1057524898
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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 RCV000445512 SCV002499518 likely pathogenic Monogenic diabetes 2022-04-11 reviewed by expert panel curation 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.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine RCV000445512 SCV000537087 uncertain significance Monogenic diabetes 2015-12-04 criteria provided, single submitter research ACMG Criteria: PM1 (HOX DNA binding domain), PM2, PP3
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002463446 SCV002604984 likely risk allele 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 rs1057524898 with MODY3.

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