Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001984920 | SCV002212815 | uncertain significance | Atrioventricular septal defect 4 | 2023-01-09 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with tetralogy of fallot (PMID: 26490186). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1435477). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change falls in intron 4 of the GATA4 gene. It does not directly change the encoded amino acid sequence of the GATA4 protein. It affects a nucleotide within the consensus splice site. |
| Victorian Clinical Genetics Services, |
RCV002272533 | SCV002557836 | uncertain significance | Testicular anomalies with or without congenital heart disease | 2021-05-06 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with GATA4-related disorders. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same noncanonical splice site, is present in gnomAD (v2) at a frequency of 0.00002 (6 heterozygotes, 0 homozygotes). (I) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in one individual. This variant has not been previously reported in the literature in association with a disorder of sex development and the gene-disease association is not well established (Panel App Australia; PMIDs: 21220346, 30455927, 29735817, 27899157). However, it has been reported in a patient with Tetralogy of Fallot (PMID: 26490186). (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) 1205 - This variant has been shown to be maternally inherited (VCGS 20G002519/ by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |