Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV002272027 | SCV002557871 | likely benign | 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 Likely Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with GATA4-related cardiac disease. (I) 0107 - This gene is associated with autosomal dominant disease. A number a different cardiac conditions are caused by variants in GATA4, however association with differences of sex development (DSD) is not well-established (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to glutamine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of GATA4-related cardiac disease (gnomAD (v2) 132 heterozygotes, 0 homozygotes). (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (17 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated zinc finger DNA binding domain (NCBI). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Alternative changes at the same residue, to alanine and arginine, have previously been classified as VUS in relation to atrioventricular septal defect (ClinVar). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting for both cardiac and DSD conditions, however more recent reports consistently report the variant as benign in relation to DSD (ClinVar, LOVD, HGMD, OMIM, PMID: 32992319). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Gene |
RCV001555802 | SCV001777271 | uncertain significance | not provided | 2025-05-16 | criteria provided, single submitter | clinical testing | Identified in association with early onset diabetes and variations of sex characteristics, including individuals without heart anomalies (PMID: 27899157, 27810688, 29735817); Identified in several individuals with congenital heart defects (PMID: 18672102, 19678963, 21110066, 20654103, 21631294, 26490186, 28161810, 28372585, 30152191, 31115957, 38456293); Identified in two siblings with developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome who where compound heterozygous for two NARS2 variants (PMID: 35703918); Functional studies show inconsistent data, including one study that found p.(P407Q) results in ~50% reduction in transactivation compared to wild type protein whereas another study showed protein behavior similar to wild type (PMID: 29735817, 31962012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19678963, 26490186, 24583203, 21110066, 20654103, 20592452, 22648249, 22959235, 26997702, 27899157, 28161810, 28372585, 29735817, 30152191, 31115957, 21631294, 31513339, 31962012, 34426522, 32508047, 27810688, 18672102, 35703918, 35863714, 35047139, 38375489, 38456293, 38274337) |
| Laboratory for Molecular Medicine, |
RCV001195378 | SCV001365727 | uncertain significance | not specified | 2019-01-31 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 TOF patient (sporadic) (Zhang 2008), in 3 individuals (het) with disorders of sexual develpment (Eggers 2016). Liu 2017 further reported this variant in 4/600 patients with conotruncal heart defects and 1/300 controls. Qian 2017 reported the variant in 2 individuals with TOF and POF (also carried V380M, previously associated with VSD))). Identified in 0.3% of East Asian chromosomes in gnomAD. Present in ClinVar (ID 30103) with conflicting interpretations (B, Uncertain significance). |
| Labcorp Genetics |
RCV000526826 | SCV000651999 | benign | Atrioventricular septal defect 4 | 2026-01-25 | criteria provided, single submitter | clinical testing | |
| Soonchunhyang University Bucheon Hospital, |
RCV000490358 | SCV000267333 | uncertain significance | Atrial septal defect 2; Ventricular septal defect 1; Atrioventricular septal defect 4 | 2016-03-18 | criteria provided, single submitter | reference population | |
| OMIM | RCV000030949 | SCV006554563 | pathogenic | Ventricular septal defect 1 | 2010-12-01 | no assertion criteria provided | literature only | |
| Department of Pediatrics, |
RCV001252768 | SCV001163911 | uncertain significance | Microcephaly | no assertion criteria provided | research | ||
| Reproductive Development, |
RCV001007695 | SCV001146892 | benign | 46,XY sex reversal 3 | 2019-08-26 | no assertion criteria provided | research | |
| OMIM | RCV000023008 | SCV000044299 | pathogenic | Tetralogy of Fallot | 2010-12-01 | no assertion criteria provided | literature only |