Submissions for variant NM_005149.3(TBX19):c.204-3T>C

gnomAD frequency: 0.00069  dbSNP: rs200043223

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000291762	SCV000350422	uncertain significance	Congenital isolated adrenocorticotropic hormone deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000430457	SCV000522504	likely benign	not specified	2016-01-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000291762	SCV000805088	benign	Congenital isolated adrenocorticotropic hormone deficiency	2018-06-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000994162	SCV001147503	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	TBX19: PM2, PM3:Supporting, BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000994162	SCV003273476	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the TBX19 gene. It does not directly change the encoded amino acid sequence of the TBX19 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200043223, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TBX19-related conditions. ClinVar contains an entry for this variant (Variation ID: 293456). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003910063	SCV004723972	likely benign	TBX19-related disorder	2019-08-01	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).