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

CA16621222

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
NC_000023.11:g.153691556_153691559del
CM000685.2:g.153691556_153691559del
NC_000023.10:g.152957011_152957014del
CM000685.1:g.152957011_152957014del
NC_000023.9:g.152610205_152610208del
NG_012016.1:g.8260_8263del
NG_012016.2:g.8260_8263del
ENST00000253122.10:c.644+3_644+6del
ENST00000675713.1:n.398+3_398+6del
ENST00000253122.9:c.644+3_644+6del
ENST00000429147.1:c.93+3_93+6del
ENST00000430077.6:c.299+3_299+6del
ENST00000466243.1:n.436+3_436+6del
ENST00000467402.1:n.145+49_145+52del
NM_001142805.1:c.644+3_644+6del
NM_001142806.1:c.299+3_299+6del
NM_005629.3:c.644+3_644+6del
NM_001142805.2:c.644+3_644+6del

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting

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

• 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).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).