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Gene-disease assertions not curated here (add link or write note):

Disease

Congenital isolated adrenocorticotropic hormone deficiency

Inheritance

Autosomal recessive

Prevalence

 unknown

Source:

Rapid or full curation?

  • Rapid - molecular mechanism only needed
  • Full

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

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

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

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

 Options

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

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

 Examples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

Case ID, Curator name, Date, Jira ticket link

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