ClinGen Dosage Sensitivity Curation Page

SLC6A8

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

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.