ClinGen Dosage Sensitivity Curation Page

GLA

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
  • Haploinsufficiency Phenotype: FABRY DISEASE
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

Loss of function pathogenic variants in GLA is associated with Fabry disease, an X-linked lysosomal storage disorder resulting from deficient or absent activity of alpha-galactosidase A enzyme. The classic form, occurring in males with less than 1% ?-Gal A enzyme activity, usually has its onset in childhood or adolescence with typical phenotype including severe pain in the extremities, vascular cutaneous lesions, sweating abnormalities, characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in the third to fifth decade . Heterozygous females can display symptoms, but these are typically milder and at a later age of onset than males (See Genereviews for more details) More than 800 GLA pathogenic variants have been identified. Currently the genotype-phenotype correlations data is limited because most families with Fabry disease have a private pathogenic variant, and there is significant phenotypic variability even among individuals with the same pathogenic variant.

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.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Focal duplication of GLA is not identified.

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.