Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV003225135 | SCV003921995 | likely pathogenic | Kallikrein, decreased urinary activity of | criteria provided, single submitter | clinical testing | Evidence in support of pathogenic classification: - Variant is absent from gnomAD (both v2 and v3). - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. - This variant has limited previous evidence of pathogenicity in unrelated individuals. Two unrelated pairs of siblings with pancreatic agenesis without cerebellum pathology (MIM#615953) have been reported with this variant. This variant has been described as a hypomorphic allele (PMID: 27284104). - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies demonstrated residual transactivational activities and residual PTF1A:E12 dimer formation (PMID: 27284104). Additional information: - Loss of function is a known mechanism of disease in this gene and is associated with pancreatic agenesis, with and without cerebellar agenesis (MIM#609069 and 615953, respectively). Typically, individuals with null variants in this gene are described to have cerebellar pathology. However, all four individuals described so far to harbour the p.(Pro191Thr) variant, which has been shown to have residual activity (see above), have isolated pancreatic agenesis only (PMID: 28663161, 27284104). - This gene is associated with autosomal recessive disease. - Variant is predicted to result in a missense amino acid change from proline to threonine. - This variant is homozygous. - Variant is located in the annotated helix-loop-helix domain (PMID: 27284104; NCBI). - No comparable missense variants have previous evidence for pathogenicity. - This variant has limited evidence for segregation with disease. Two unrelated pairs of siblings as detailed above. - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). | |
| Genomic Medicine Center of Excellence, |
RCV003227879 | SCV003924349 | pathogenic | Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome | 2023-05-08 | criteria provided, single submitter | research | |
| Biochemical Molecular Genetic Laboratory, |
RCV000984966 | SCV001132886 | pathogenic | Pancreatic agenesis 2 | 2019-08-25 | no assertion criteria provided | clinical testing | |
| Clinical Laboratory Sciences Program |
RCV003227879 | SCV003927822 | likely pathogenic | Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome | 2023-04-01 | no assertion criteria provided | clinical testing |