ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.441C>A (p.His147Gln)

dbSNP: rs193922597
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV002222008 SCV002499504 uncertain significance Monogenic diabetes 2022-04-08 reviewed by expert panel curation The c.441C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to glutamine at codon 147 (p.(His147Gln)) 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 0.938, which is greater than the MDEP threshold of 0.70 (PP3). In summary, c.441C>A 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 September 30, 2021): PP3, PM2_P, PM1.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030502 SCV000053173 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 RCV002319431 SCV002604961 uncertain 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 rs193922597 with MODY3.
Labcorp Genetics (formerly Invitae), Labcorp RCV003546460 SCV004262652 uncertain significance not provided 2024-01-13 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 147 of the HNF1A protein (p.His147Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HNF1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 36821). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1A protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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