ClinVar Genomic variation as it relates to human health

This premature translational stop signal has been observed in individual(s) with cystic kidney (PMID: 31131422). ClinVar contains an entry for this variant (Variation ID: 12640). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg276*) in the HNF1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1B are known to be pathogenic (PMID: 9398836, 12148114, 15068978, 20378641).

Variant summary: HNF1B c.826C>T (p.Arg276X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.826C>T has been reported in the literature in at least one individual affected with Maturity Onset Diabetes Of The Young 5 (Renal Cysts And Diabetes Syndrome) (example: Ge_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35846334). ClinVar contains an entry for this variant (Variation ID: 12640). Based on the evidence outlined above, the variant was classified as pathogenic.

A heterozygous nonsense variant, NM_000458.3(HNF1B):c.826C>T, has been identified in exon 4 of 9 of the HNF1B gene. The variant is predicted to result in a premature stop codon at position 276 of the protein (NP_000449.1(HNF1B):p.(Arg276*)). This variant is predicted to result in loss of protein function through nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is absent in population databases (gnomAD, 1000G). The variant has been previously described as pathogenic and segregated with disease in at least one family with renal cysts and diabetes syndrome (MODY5) (ClinVar; Furuta, H. et al., 2002; Fujimoto, K. et al., 2007; Verhave, J.C., 2016). Functional analysis showed that the mutant allele produces inactive protein (Furuta, H. et al., 2002). In addition, p.(Arg276*) caused significant decrease in glucose-stimulated insulin secretion in MIN6 cells (Fujimoto, K. et al., 2007). Several truncating variants up and downstream predicted to result in NMD have been reported pathogenic (ClinVar, HGMD, Decipher). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

The stop gained p.R276* in HNF1B (NM_000458.4) has been reported previously in affected patients (Furuta H et al; Fujimoto K et al).Functional studies reveal a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The p.R276* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.

This variant is expected to result in the loss of a functional protein. This variant has been identified in at least one individual with MODY or renal cysts. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12161522, 31131422, 17878605, 32939031, 33226606, 35592779, 35992134)