Submissions for variant NM_000458.4(HNF1B):c.529C>T (p.Arg177Ter)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000013470	SCV000926111	pathogenic	Renal cysts and diabetes syndrome	2019-07-06	criteria provided, single submitter	literature only
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000013470	SCV001427175	pathogenic	Renal cysts and diabetes syndrome	2019-02-08	criteria provided, single submitter	clinical testing	A heterozygous nonsense variant, NM_000458.4(HNF1B):c.529C>T, has been identified in exon 2 of 9 of the HNF1B gene. The variant is predicted to result in a premature stop codon at position 177 of the protein (NP_000449.1(HNF1B):p.(Arg177*)). This variant is predicted to result in loss of protein function through nonsense-mediated decay (Yabe, S. G. et al., 2015), which is a reported mechanism of pathogenicity for this gene. The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic in patients with maturity-onset diabetes of the young, MODY5 (ClinVar; Horikawa, Y. et al., 1997; Montoli, A. et al., 2002). It has also been shown to segregate with the disease in at least one family (Horikawa, Y. et al., 1997). Additionally, studies show impaired localisation and altered protein function (Horikawa, Y. et al., 1997; Tomura, H. et al., 1999; Gu, N. et al., 2006; Barbacci, E. et al., 2004). Several truncating variants have been reported pathogenic (ClinVar, Decipher). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Invitae	RCV001851826	SCV002205303	pathogenic	not provided	2023-03-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 12635). This premature translational stop signal has been observed in individual(s) with clinical features of renal cysts and diabetes syndrome (PMID: 9398836, 12148114). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg177*) 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).
GeneDx	RCV001851826	SCV002576208	pathogenic	not provided	2022-09-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect due to a loss of transactivation activity, as well as a dominant negative effect and altered protein localization specific to certain cell types (Tomura et al., 1999); 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9398836, 12148114, 31131422, 32939031, 10224045)
Fulgent Genetics, Fulgent Genetics	RCV002496342	SCV002785178	pathogenic	Renal cysts and diabetes syndrome; Type 2 diabetes mellitus; Nonpapillary renal cell carcinoma	2022-02-23	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001851826	SCV004026163	pathogenic	not provided	2022-11-02	criteria provided, single submitter	clinical testing
OMIM	RCV000013470	SCV000033717	pathogenic	Renal cysts and diabetes syndrome	1997-12-01	no assertion criteria provided	literature only