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

Disease

Glutaminase deficiency

Inheritance

Autosomal recessive

Prevalence

 

Source:

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - Definitive (AR), limited for (AD), 7/9/2021

Clinical Validity Scoring Notes and points

GLS was first reported in relation to autosomal recessive glutaminase deficiency in 2018 (Lynch DS, et al., 2018, PMID: 29468182). Glutaminase deficiency is characterized by refractory seizures, respiratory failure, brain abnormalities and death in the neonatal period, though milder cases with spastic ataxia-dysarthria have also been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Five unique variants (nonsense, frameshift, and missense) have been reported as well as a 5’ UTR repeat expansion (normally occurring in 8 or 16 repeats) ranging from 680 to 1500 repeats. Variants in this gene have been reported in six probands in 3 publications (PMIDs: 29468182, 30575854, 30970188), and segregated with disease in at least 2 additional family member. Experimentally, this gene-disease relationship is supported by its role in the production of glutamate, the main excitatory neurotransmitter in the central nervous system, including the brain stem respiratory center (PMID: 12963351) and a mouse model with partial recapitulation of disease (PMID: 16641247). In summary GLS is definitively associated with autosomal recessive glutaminase deficiency.

Source: ClinGen

Clinical Validity Points Total

Source:

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Definitive

Source: ClinGen

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / decreased expression / methylation

Triplet repeat expansion

GCA. in 5’UTR

GeneReviews: Normal: 5-38, Full penetrance pathogenic 680-1500 https://www-ncbi-nlm-nih-gov.ezp-prod1.hul.harvard.edu/books/NBK535148/

STRchive: "normal":"5-26", "pathogenic":"90 - 1500", "pathogenic_min":90.0, "pathogenic_max":1500.0

stripy - normal 5-26, ≥680

GnomAD - Normal ≤ 26, Pathogenic ≥ 680

van Kuilenburg 2019 PMID: 30970188

  • Three probands with early onset motor delay, speech delay, ataxia. Elevation in plasma glutamine, normal plasma ammonia levels. All three had expansions of the GCA repeat in the 5' UTR of GLS found in their blood samples (sized 680, 900, and 1500). Smaller repeats in fibroblasts consistent w/ somatic heterogeneity. To investigate normal repeat size 8295 genomes showed median size of 14 repeats, . Only 1 was het for an allele w/ more than 90 repeats

Fazal 2023 PMID: 35913761

  • Describes two families with Glutaminase deficiency. One with a complex structural change w/ a homozygous repeat expansion nested within a quadruplication event

35913761

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)

Early childhood (2-4)

Source: STRchive (PMID: 30970188, 35913761)

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

  • Early onset gross and fine motor delay

  • speech delay

  • Ataxia (broad, ataxic gait)

  • Normal brain MRI (or cerebellar atrophy at advanced stage)

  • Progressive neuro deterioration

  • tremor, dysarthria

  • Optic atrophy

  • Metabolic testg: High plasma glutamine. Normal plasma ammonia, urinary organic acids and acylcarnities,

Sources: PMID: 30970188, 35913761

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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