ClinVar

Description

The NM_005629.4:c.1210G>C variant in SLC6A8 is predicted to result in the substitution of alanine by proline at amino acid 404 (p.Ala404Pro). A 3 year old male, hemizygous for this variant, with clinical features consistent with creatine transporter deficiency has been reported who also had elevated urine creatine/creatine on three occassions, reduced creatine peak on brain MRS, and 6% normal creatine uptake in fibroblasts (with 25 uM creatine) (PP4_Strong). The variant was not identified in either of two independent samples from the patient's mother (PM6). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.601 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function. SpliceAI predicts that the variant has no impact on splicing. To our knowledge, the results of functional studies on this variant have not been reported. In summary, this variant meets the criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PP4_Strong, PM6, PM2_Supporting. (Classification approved by the ClinGen CCDS, June 21, 2023)