Submissions for variant NM_001002295.2(GATA3):c.431dup (p.His145fs)

dbSNP: rs1588377948

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089964	SCV001244995	pathogenic	Hypoparathyroidism, deafness, renal disease syndrome	2018-08-28	criteria provided, single submitter	clinical testing	A heterozygous frameshift duplication variant, NM_001002295.1(GATA3):c.431dupG, has been identified in exon 3 of 6 of the GATA3 gene. This duplication is predicted to create a frameshift starting at amino acid position 145, introducing a stop codon 159 residues downstream (NP_001002295.1(GATA3): p.(His145Profs*159)). This variant is predicted to result in loss of protein function either through truncation (including the loss of 2 GATA zinc finger domains) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is absent in population databases (gnomAD, dbSNP, 1000G). This variant has previously been reported in one patient with HDR syndrome (Saito T. et al. 2009). Additionally, other truncating variants have previously been reported as disease causing (ClinVar, Ali A. et al. (2007)). Analysis of parental samples indicated this variant was maternally inherited. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862666	SCV002135846	pathogenic	not provided	2022-09-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His145Profs*159) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 870395). This variant is also known as 432insG. This premature translational stop signal has been observed in individual(s) with GATA3-related conditions (PMID: 19057839). This variant is not present in population databases (gnomAD no frequency).
Fulgent Genetics, Fulgent Genetics	RCV001089964	SCV005682835	likely pathogenic	Hypoparathyroidism, deafness, renal disease syndrome	2024-02-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003892163	SCV004712180	pathogenic	GATA3-related disorder	2023-10-30	no assertion criteria provided	clinical testing	The GATA3 c.431dupG variant is predicted to result in a frameshift and premature protein termination (p.His145Profs*159). This variant has been reported in at least two individuals with hypoparathyroidism and/or deafness (Saito et al 2008. PubMed ID: 19057839; See Patient A5 in eTable 3 in Australian Genomics Health Alliance Acute Care Flagship. et al 2020. PubMed ID: 32573669). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in GATA3 are expected to be pathogenic. This variant is interpreted as pathogenic.