Disease | Glutaminase deficiency |
|---|
Inheritance | Autosomal recessive |
Prevalence | Source: |
Rapid or full curation? | |
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 | Expand |
|---|
| title | Classifications (pts) |
|---|
| Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
| Definitive Source: ClinGen |
Molecular Mechanism | Expand |
|---|
| Loss of function Gain of function Dominant negative Unknown Other |
| Loss of function / decreased expression / methylation Variant spectrum includes truncations, missense, triplet repeat expansions Triplet repeat expansion of GCA . in 5’UTR Normal: 5-26 Pathogenic: ≥524
Cutoff: Since there is such a large gap, suggest using a cutoff of ~40 (since this will reduce false positives for VA review, based on data in gnomAD). However Nirvana’s annotation sets normal range of 0-89. This cutoff is not really appropriate, as EH is not accurate when sizing alleles ~50 repeats and larger. Sources: PMID: 30970188, 35913761 STR Review notes: 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 . Using ExpansionHunter, patient 1 was found to have an allele of more than 90 alleles (THIS IS WHERE THE CUTOFF OF 90 FOR EXPANDED ALLELES COMES FROM). Triplet repeat primed PCR performed on blood revealed that 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 35913761 |
Penetrance | Expand |
|---|
| Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | Source: |
Age of Onset | Expand |
|---|
| Congenital Pediatric Adolescent Adulthood Late adulthood |
(list source/PMID) | Early childhood (2-4) Source: STRchive (PMID: 30970188, 35913761) |
Severity | Expand |
|---|
| 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. |
| Severe |
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, strabismus Epilepsy 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 | Expand |
|---|
| - 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 | Andrea Oza 05.06.24 | Jira Legacy |
|---|
| server | System Jira |
|---|
| serverId | eee25142-2510-336f-918a-865682ebdf2e |
|---|
| key | BCL-168 |
|---|
|
|