Variant: NM_005629.4(SLC6A8):c.644+3_644+6del

421767 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: 2a363732-aaaa-4b2a-a411-6841e2713d12

Approved on: 2023-08-24

Published on: 2023-08-24

HGVS expressions

NM_005629.4:c.644+3_644+6del
NM_005629.4(SLC6A8):c.644+3_644+6del

Uncertain Significance

• Met criteria codes: PM2_Supporting PP3

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 1.1.0

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_005629.4:c.644+3_644+6 del variant in SLC6A8, is in the region of the donor splice site of intron 3. The computational splicing predictors SpliceAI and varSEAK both predict that the variant disrupts the donor splice site of intron 3. SpliceAI gives a score of 0.97 for donor loss, and varSEAK gives a prediction of Class 5 (i.e. "splicing effect) with "Loss of function for authentic Splice Site" (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, there are no published reports describing this variant in individuals with features of creatine transporter deficiency, and the results of functional studies are unavailable. There is a ClinVar entry for this variant (Variation ID:421767). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP codes met, as specified by the ClinGen CCDS VCEP (specifications Version 1.0): PP3, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on January 12, 2023).

Met criteria codes

• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PP3: The computational splicing predictors SpliceAI and varSEAK both predict that the variant disrupts the donor splice site of intron 3. SpliceAI gives a score of 0.97 for donor loss, and varSEAK gives a prediction of Class 5 (i.e. "splicing effect) with "Loss of function for authentic Splice Site" (PP3).