ClinVar Genomic variation as it relates to human health

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 47 of the HNF1B protein (p.Pro47Leu). This variant is present in population databases (rs193922483, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HNF1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 36840). 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 HNF1B 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.

Variant summary: The variant, HNF1B (legacy name TCF2) c.140C>T (p.Pro47Leu) results in a non-conservative amino acid change located in the N terminal of Hepatocyte nuclear factor 1 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 245772 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.140C>T in individuals affected with Maturity Onset Diabetes of the Young 5 (Renal Cysts and Diabetes Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.Pro47Leu variant in HNF1B has been reported in at least 1 individual with Renal Cysts and Diabetes Syndrome in ClinVar (Variation ID: 36840), and has been identified in 0.02024% (7/34580) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922483). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36840). 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, the clinical significance of the p.Pro47Leu variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3 (Richards 2015).

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: 28215227)