Submissions for variant NM_000458.4(HNF1B):c.703C>T (p.Arg235Trp)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030532	SCV000053203	likely pathogenic	Renal cysts and diabetes syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000030532	SCV000926094	likely pathogenic	Renal cysts and diabetes syndrome	2019-07-06	criteria provided, single submitter	literature only
Molecular Biology Laboratory, Fundació Puigvert	RCV000030532	SCV001425091	likely pathogenic	Renal cysts and diabetes syndrome	2020-02-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852606	SCV002265600	uncertain significance	not provided	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 235 of the HNF1B protein (p.Arg235Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of HNF1B-related conditions (PMID: 24698406, 26669242, 33532864). This variant is also known as p.Arg234Trp. ClinVar contains an entry for this variant (Variation ID: 36851). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF1B protein function. 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.
Athena Diagnostics	RCV001852606	SCV004229335	uncertain significance	not provided	2022-12-13	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. This variant has been identified in at least one individual with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) The variant is located in a region that is considered important for protein function and/or structure.
PreventionGenetics, part of Exact Sciences	RCV004730858	SCV005337629	uncertain significance	HNF1B-related disorder	2024-04-30	no assertion criteria provided	clinical testing	The HNF1B c.703C>T variant is predicted to result in the amino acid substitution p.Arg235Trp. This variant has been reported in individuals with mature onset diabetes of the young; in at least two instances, a family history of diabetes was noted (Dusatkova et al. 2014. PubMed ID: 24698406; Table 2, Ağladıoğlu et al. 2016. PubMed ID: 26669242; Table S5, Johnson et al. 2018. PubMed ID: 30191644). This variant has also been reported, along with a PKD1 missense variant, in an individual with bilateral renal cysts and chronic kidney disease (Table S2, Domingo-Gallego et al. 2022. PubMed ID: 33532864). This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this 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.