ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.343G>T (p.Val115Leu)

dbSNP: rs1876667856
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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 RCV004733216 SCV005367829 likely pathogenic Monogenic diabetes 2024-09-10 reviewed by expert panel curation The c.343G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to leucine at codon 115 (p.(Val115Leu)) 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 was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; ClinVar, internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.902, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.343G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PS4_Moderate, PP3, PP4, PM2_Supporting.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001248888 SCV001422568 uncertain significance Maturity-onset diabetes of the young type 3 2020-01-22 criteria provided, single submitter curation The p.Val115Leu variant in HNF1A has been reported in at least 1 individual with maturity-onset diabetes of the young (PMID: 16917892), and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015).
Geisinger Clinic, Geisinger Health System RCV001248888 SCV002562132 likely pathogenic Maturity-onset diabetes of the young type 3 2022-08-02 criteria provided, single submitter research PM2, PP3, PP4, PS4_Moderate, PM5
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002327605 SCV002601729 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 rs1876667856 with MODY3.

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