ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.803T>C (p.Phe268Ser)

dbSNP: rs193922605
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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 RCV001794464 SCV002032354 likely pathogenic Monogenic diabetes 2024-08-07 reviewed by expert panel curation The c.803T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of phenylalanine to serine at codon 268 (p.(Phe268Ser)) of NM_000545.8. This variant is located within the DNA binding domain of HNF1A (codons 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.986 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), but was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 27634015, PMID: 15305805, ClinVar ID 36831, internal lab contributors). The MODY probability is unable to be calculated due to lack of clinical information (PMID: 27634015, PMID: 15305805, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (PS2_Moderate; internal lab contributor). Two other missense variants, c.802T>A p.(Phe268Ile) and c.802T>C p.(Phe268Leu) do not meet the criteria to be classified as likely pathogenic or pathogenic by the ClinGen MDEP without the addition of PM5 from this variant; therefore, PM5 will not be applied. In summary, the evidence supports the classification of c.803T>C as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 8/18/2021): PS2_moderate, PS4_moderate, PP3, PM1_Supporting, PM2_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030512 SCV000053183 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 RCV002464081 SCV002605483 likely 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. Sufficient evidence is found to confer the association of this particular variant rs193922605 with MODY3.

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