ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.653A>G (p.Tyr218Cys)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003494038 SCV004242379 pathogenic Monogenic diabetes 2024-01-22 reviewed by expert panel curation The c.653A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to cysteine at codon 218 (p.Tyr218Cys)) 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). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in seven unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 10872540, PMID: 17286239, internal lab contributors). At least one individual had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies, and sensitive to sulfonylureas) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with at least 4 informative meioses in 4 families with MODY (PP1_Strong; PMID: 17286239, internal lab contributors). In summary, c.653A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting.

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