Submissions for variant NM_001002295.2(GATA3):c.924+1G>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471647	SCV002769067	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: 0103 - Loss of function is a known mechanism of disease in this gene and is associated with hypoparathyroidism, sensorineural deafness, and renal dysplasia (MIM#146255). In addition dominant-negative has been proven for a single missense variant (PMID: 21120445). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Both inter and intra-familial variability have been reported (OMIM). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0703 - Other canonical splice site variants comparable to the one identified in this case have limited previous evidence for pathogenicity. Two different splice site variants have been reported in two unrelated families, each with two affected individuals with hypoparathyroidism, sensorineural deafness, with/without renal dysplasia (MIM#146255) (PMID: 16912130, 27387476). (SP) 0807 - This variant has no previous evidence of pathogenicity. A pathogenic classification was noted in LOVD however, no further information was provided and therefore, it was not considered in this classification. (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). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002573613	SCV003233523	likely pathogenic	not provided	2022-08-29	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with GATA3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 of the GATA3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GATA3 are known to be pathogenic (PMID: 14985365, 21242646).