Submissions for variant NM_000545.8(HNF1A):c.415C>T (p.Leu139Phe)

dbSNP: rs1475566248

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004733383	SCV005367834	likely pathogenic	Monogenic diabetes	2024-10-02	reviewed by expert panel	curation	The c.415C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to phenylalanine at codon 139 (p.(Leu139Phe)) 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 0.903, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate, internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and persistent C-peptide over 5 years after T1D diagnosis)(PP4_Moderate; internal lab contributors). Two other missense variants, c.416T>C p.Leu139Pro and c.415C>G p.Leu139Val, have been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.415C>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): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting.
Genetic Services Laboratory, University of Chicago	RCV001817833	SCV002069294	uncertain significance	not specified	2020-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV005255690	SCV005908720	likely pathogenic	not provided	2024-10-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12453420, 18003757)
PreventionGenetics, part of Exact Sciences	RCV003892878	SCV004712212	uncertain significance	HNF1A-related disorder	2023-12-21	no assertion criteria provided	clinical testing	The HNF1A c.415C>T variant is predicted to result in the amino acid substitution p.Leu139Phe. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Different missense changes impacting the same amino acid (p.Leu139Val and p. Leu139Pro) have been reported in individuals with maturity-onset diabetes of the young (MODY) (Kwak et al. 2016. PubMed ID: 27810688; Malikova et al. 2020. PubMed ID: 32017842) and in vitro functional studies demonstrate that the Leu139Pro variant negatively affects HNF1A function (Table 1, Malikova et al. 2020. PubMed ID: 32017842). Although we suspect that the p.Leu139Phe variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.