Submissions for variant NM_000458.4(HNF1B):c.1657C>A (p.Pro553Thr)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594491	SCV000705479	uncertain significance	not provided	2018-05-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000787052	SCV000925979	uncertain significance	Renal cysts and diabetes syndrome	2019-07-06	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000594491	SCV002218786	uncertain significance	not provided	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 553 of the HNF1B protein (p.Pro553Thr). This variant is present in population databases (rs147798914, gnomAD 0.03%). This missense change has been observed in individual(s) with HNF1B-related conditions (PMID: 28420700). ClinVar contains an entry for this variant (Variation ID: 499802). 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV002497268	SCV002782714	uncertain significance	Renal cysts and diabetes syndrome; Type 2 diabetes mellitus; Nonpapillary renal cell carcinoma	2022-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000594491	SCV003853081	uncertain significance	not provided	2022-09-28	criteria provided, single submitter	clinical testing	Reported in a patient with diabetes in published literature (Dubois-Laforgue et al., 2017); clinical information was not provided; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28420700)
Ambry Genetics	RCV004619349	SCV005122023	uncertain significance	Maturity onset diabetes mellitus in young	2024-03-28	criteria provided, single submitter	clinical testing	The c.1657C>A (p.P553T) alteration is located in exon 9 (coding exon 9) of the HNF1B gene. This alteration results from a C to A substitution at nucleotide position 1657, causing the proline (P) at amino acid position 553 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (8/282558) total alleles studied. The highest observed frequency was 0.032% (8/24962) of African alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003403395	SCV004105687	uncertain significance	HNF1B-related disorder	2024-04-04	no assertion criteria provided	clinical testing	The HNF1B c.1657C>A variant is predicted to result in the amino acid substitution p.Pro553Thr. This variant was reported in an individual with diabetes, but the clinical significance was uncertain (Table S1, Dubois-Laforgue et al. 2017. PubMed ID: 28420700). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.