Submissions for variant NM_000458.4(HNF1B):c.780G>C (p.Glu260Asp)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000734628	SCV000862784	uncertain significance	not provided	2018-08-08	criteria provided, single submitter	clinical testing
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000787147	SCV000926077	uncertain significance	Renal cysts and diabetes syndrome	2019-07-06	criteria provided, single submitter	literature only
Athena Diagnostics Inc	RCV001288507	SCV001475670	benign	not specified	2020-02-13	criteria provided, single submitter	clinical testing
Invitae	RCV000734628	SCV002230474	uncertain significance	not provided	2022-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 260 of the HNF1B protein (p.Glu260Asp). This variant is present in population databases (rs536638039, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of diabetes with renal cysts (PMID: 14583183, 22051731). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 598272). 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. Experimental studies have shown that this missense change does not substantially affect HNF1B function (PMID: 14583183). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001288507	SCV004037751	uncertain significance	not specified	2023-08-30	criteria provided, single submitter	clinical testing	Variant summary: HNF1B c.780G>C (p.Glu260Asp) results in a conservative amino acid change located in the Homeobox domain (IPR001356) 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 7.4e-05 in 282886 control chromosomes, predominantly at a frequency of 0.001 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 400 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1B causing Maturity Onset Diabetes Of The Young 5 (Renal Cysts And Diabetes Syndrome) phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.780G>C has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 5 (Renal Cysts And Diabetes Syndrome) (So_2003, Wang_2011, Wu_2018, Wopperer_2022, Liu_2022) and this variant co-segregated with HNF-1b-MODY phenotype in one family (Wang_2011). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (So_2003). The following publications have been ascertained in the context of this evaluation (PMID: 14583183, 22051731, 35643372, 30548481, 36549658). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003424324	SCV004118623	uncertain significance	HNF1B-related condition	2023-06-13	criteria provided, single submitter	clinical testing	The HNF1B c.780G>C variant is predicted to result in the amino acid substitution p.Glu260Asp. This variant has been reported in patients with variable renal phenotypes or diabetes (So et al. 2003. PubMed ID: 14583183; Wang et al. 2012. PubMed ID: 22051731; Wopperer et al. 2022. PubMed ID: 35643372). However, this variant is also reported in 0.10% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-36093579-C-G). At this time, the clinical significance of this variant is uncertain.