Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV001254692 | SCV001430755 | pathogenic | Hypoparathyroidism, deafness, renal disease syndrome | 2020-05-28 | criteria provided, single submitter | research | The heterozygous p.Ser237GlnfsTer variant in GATA3 was identified by our study in 1 individual with hypoparathyroidism-deafness-renal disease syndrome (HDR syndrome). Trio exome analysis showed this variant to be de novo. The p.Ser237Glnfs variant in GATA3 has been reported in 2 Japanese and 1 European (non-Finnish) individual with HDR Syndrome (PMID: 30143558, 30396722), and data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 237 and leads to a premature termination codon 67 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. While there is some evidence to suggest that heterozygous loss of function of the GATA3 gene is a disease mechanism in HDR Syndrome, this association is not yet strongly established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, this variant meets criteria to be classified as pathogenic for HDR Syndrome in an autosomal dominant manner based on predicted loss of function of the gene and de novo occurrence of the variant in an affected individual. ACMG/AMP Criteria applied: PVS1_strong, PS2, PS4_supporting (Richards 2015). |
| Invitae | RCV002570570 | SCV003441477 | pathogenic | not provided | 2022-05-01 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ser237Glnfs*67) in the GATA3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GATA3 are known to be pathogenic (PMID: 14985365, 21242646). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with GATA3-related conditions (PMID: 30396722, 33120464). ClinVar contains an entry for this variant (Variation ID: 977148). For these reasons, this variant has been classified as Pathogenic. |