ClinGen Dosage Sensitivity Curation Page

SLC6A8

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
29478817 Joncquel-chevalier et al. (2018) did functional assessment of creatine transporter in 8 patients (4 males and 4 females) with splicing (N=3), small deletions (N=3) or missense variants (N=2) and equal number of controls, and proposed an easy, reliable and discriminative manner for exploring creatine transporter activity and disease variations.
23644449 Van de Kamp et al. (2013) did a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic variant in the creatine transporter gene (SLC6A8). A third of patients had a de novo variant in the SLC6A8 gene. The spectrum of variants in these patients are missense (N=26/85 families), in-frame (N=20/85 families), frame shift (N=15/80 families), nonsense (11/85 families), splicing (9/85 families), and multi-exon deletions (4 unrelated patients). The authors propose that missense variants with residual activity might be associated with a milder phenotype, and large deletions extending beyond the 3' end of the SLC6A8 gene are typically associated with a more severe phenotype.
23660394 Comeaux et al (2013) presented the biochemical and molecular testing results for 122 CCDS patients, with focus on 3 related genes: AGAT (N=20)and GAMT(N=33) for creatine biosynthesis disorders and SLC6A8 N=69, both males and females) for creatine transporter (CT1) deficiency. 26 patients (25 males and 1 female) were found to harbor deleterious mutations in the SLC6A8 gene, including nonsense, splicing, frameshift, partial/whole gene deletions.

Haploinsufficiency phenotype comments:

Loss of function mutations in SLC6A8 are responsible for creatine transport deficiency in males. Female carriers can be asymptomatic or may have milder phenotype including seizures and learning disabilities. Over 60 loss-of-function variants in this gene have been reported in the medical literature, including those mentioned in the publications listed here. Additional evidence includes: PMID: 20717164 Betsalel (2011): Multiple patients reported with splicing, nonsense, and frameshift variants. In this paper, the authors discuss the creation of an LOVD database for this gene. PMID: 16601897 Anselm (2006): Report of two patients with creatine transporter deficiency who had deletions of SLC6A8. Patient 1 had a de novo deletion of exons 8-13. Patient 2 had deletion of the entire gene, but the breakpoints were not well defined, and the deletion may have included adjacent genes. PMID: 11326334 Salomens (2001): First report of a patient with creatine transporter deficiency who had a nonsense mutation in SLC6A8. His mother and grandmother were carriers and had histories of learning disability.

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:

No evidence of triplosensitivity.

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.