Inheritance

Autosomal recessive

Prevalence

 unknown

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none. GenCC - Definitive (Ambry), Strong (Invitae). No scoring needed.

Clinical Validity Scoring Notes and points

n/a

Source:

Clinical Validity Points Total

n/a

Source:

Clinical Validity Classification

Molecular Mechanism

Loss of function

1. c.82C>T p.Q28* - NMD+, but variant at high-ish frequency in gnomAD in 0.1% (104/64032) European chr. in family I, segregates in affected sib, both unaffected parents and unaffected sibs are het only. Patients from this cohort had neonatal-onset ACTH deficiency in the absence of other pituitary hormone deficiency and any identified cause of hypocortisolism (PMID: 15613420)

2. c.856C>T p.R286* - NMD +, low enough frequency in gnomAD for AR disease 0.001% (21/1180034) European chr. Present in family IV. Patients from this cohort had neonatal-onset ACTH deficiency in the absence of other pituitary hormone deficiency and any identified cause of hypocortisolism (PMID: 15613420)

3. c.535C>T p.R179* - Grpmax 0.00004700 (69/1179872) in gnomAD. Variant homozygous in patient 1 from family 1. PMID: 12651888

4. Homozygous null mouse model had very low, but detectable plasma ACTH (PMID: 12651888)

PMID: 15613420, 12651888

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

The TBX19 gene is associated with autosomal recessive congenital isolated adrenocorticotropic hormone deficiency. It is characterized by very low plasma ACTH levels and very low plasma cortisol levels. It presents with severe hypoglycemia in the neonatal period that can result in seizures. Affected individuals may also have cholestasis and/or jaundice (PMID: 15613420, 12651888).

Case ID, Curator name, Date, Jira ticket link

AO 01.13.2025 2106076990 SM-MPQ1F D-101206607-BH-4159-P-A