Submissions for variant NM_005149.3(TBX19):c.535C>T (p.Arg179Ter)

gnomAD frequency: 0.00004  dbSNP: rs200197424

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000406538	SCV000350424	uncertain significance	Congenital isolated adrenocorticotropic hormone deficiency	2017-11-13	criteria provided, single submitter	clinical testing	The TBX19 c.535C>T (p.Arg179Ter) is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg179Ter variant has been reported in a single study in which it was identified in a homozygous state in one individual with neonatal onset ACTH deficiency and in a heterozygous state in the unaffected consanguineous parents (Pulichino et al. 2003). Control data are unavailable for this variant, which is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and potential impact of stop-gained variants, the p.Arg179Ter variant is classified as a variant of unknown significance, but suspicious for pathogenicity, for ACTH deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001859755	SCV002237791	pathogenic	not provided	2022-05-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg179*) in the TBX19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBX19 are known to be pathogenic (PMID: 22170728). This variant is present in population databases (rs200197424, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with isolated adrenocorticotropic hormone deficiency (PMID: 12651888, 33423260). ClinVar contains an entry for this variant (Variation ID: 293458). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001859755	SCV003930912	pathogenic	not provided	2023-06-09	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 15613420, 31589614, 33423260, 33098107, 12651888)
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000406538	SCV000805091	pathogenic	Congenital isolated adrenocorticotropic hormone deficiency	2014-05-28	no assertion criteria provided	clinical testing