ClinGen Dosage Sensitivity Curation Page

GLA

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
27560961 Pan et al. (2016) evaluated 73 Chinese Fabry disease patients. Overall, 47 variants (considered to be pathogenic) were identified in 58 families, including 4 unique nonsense variants, 1 splice variant, and at least 7 different frameshift variants among classically affected individuals. For male patients, those with frameshift and nonsense mutations presented the classical FD, whereas those with missense mutations presented both of classical and atypical phenotypes.
30988410 Kobayashi M et al (2019) examined the mutation spectrum of the GLA gene among patients from 115 Japanese families with Fabry disease. In total, 73 different disease-causing mutations were identified: 41 missense (56.2%), 11 nonsense (15.1%), four in frame deletion (5.5%), 10 frameshift (13.7%), six splice site (8.2%), and one intronic (1.4%) mutations. The GLA mutations detected in later-onset phenotype patients with end-stage renal disease overlapped with those seen in classical patients, indicating that it is difficult to differentiate between these two phenotypes from gene mutations.
11322659 Ashley GA et al (2001) evaluated the GLA mutation spectrum in 40 unrelated families with the classical phenotype (absent alpha-Gal A activity). The data revealed 20 novel and 17 previously reported mutations. Among these 37 pathogenic variants, there were 8 nonsense variants and 6 frameshift variants.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Evidence for Triplosenstive Phenotype

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.