Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Genetics, |
RCV002221391 | SCV002498625 | pathogenic | Renal cysts and diabetes syndrome | 2021-07-02 | criteria provided, single submitter | clinical testing | This sequence change is a deletion of 1 bp in exon 3 (of 9) of HNF1B that is predicted to create a premature termination codon at position 264 (p.(Ser210Valfs*55)). It is expected to result in nonsense mediated decay in a gene where loss of function is an established mechanism of disease (ClinGen). The variant is absent in a large population cohort (gnomAD v2.1 and v3.1). It has been identified in at least two individuals with renal cysts (LOVD, Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4_Supporting, PM2_Supporting. |
| Victorian Clinical Genetics Services, |
RCV002221391 | SCV002768077 | pathogenic | Renal cysts and diabetes syndrome | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function, and gain of function are all reported mechanisms of disease in this gene and are associated with type 2 diabetes mellitus (MIM#125853) and renal cysts and diabetes syndrome (MIM#137920; OMIM, PMID: 25536396, 11845238, 15509593). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is significant inter- and intrafamilial variability of HNF1B nephropathy (PMID: 33305128). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity. It was detected in an individual with renal cysts by Centre Hospitalier Universitaire de Limoges (LOVD). (SP) 1205 - This variant has been shown to be maternally inherited. Mother has renal cysts. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |