Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV002273238 | SCV002557982 | pathogenic | Hypoparathyroidism, deafness, renal disease syndrome | 2022-09-02 | 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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypoparathyroidism, sensorineural deafness, and renal dysplasia (MIM#146255). It should also be noted that dominant-negative has been demonstrated as a mechanism of disease, associated with one missense variant within the zinc-finger domain (PMID: 21120445). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra- and inter-familial variability have been reported (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to a leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the region encompassing the well-established functional zinc-finger binding domains which has also been suggested as a pathogenic missense variant hotspot (PMID: 32442337). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Arg299Gln) variant has previously been reported in two families with hypoparathyroidism, deafness, and renal dysplasia with functional studies demonstrating that this variant abolished promoter activity and gene expression (PMIDs: 26514990, 27387476). Additionally, the p.(Arg299Trp) variant has been identified in one individual with clinical features of hypoparathyroidism, deafness, and renal dysplasia syndrome and classified as likely pathogenic by one clinical diagnostic laboratory (ClinVar). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (segregation testing). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Labcorp Genetics |
RCV003565510 | SCV004318238 | uncertain significance | not provided | 2023-10-05 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 299 of the GATA3 protein (p.Arg299Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GATA3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1699381). 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 expected to disrupt GATA3 protein function. This variant disrupts the p.Arg299 amino acid residue in GATA3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26514990, 27387476; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |