Variant: NM_005629.4(SLC6A8):c.259G>A (p.Gly87Arg)

CA256012

11700 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: f7ed3567-7588-4422-8abd-3a935cec7f43

Approved on: 2023-08-24

Published on: 2023-08-24

HGVS expressions

NM_005629.4:c.259G>A
NM_005629.4(SLC6A8):c.259G>A (p.Gly87Arg)
NC_000023.11:g.153688833G>A
CM000685.2:g.153688833G>A
NC_000023.10:g.152954288G>A
CM000685.1:g.152954288G>A
NC_000023.9:g.152607482G>A
NG_012016.1:g.5537G>A
NG_012016.2:g.5537G>A
ENST00000253122.10:c.259G>A
ENST00000253122.9:c.259G>A
ENST00000458354.5:c.-21C>T
ENST00000476466.1:n.111G>A
ENST00000480693.1:n.46C>T
NM_001142805.1:c.259G>A
NM_005629.3:c.259G>A
NM_001142805.2:c.259G>A

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting PS3_Supporting

• Not Met criteria codes: PS1 PP4

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_005629.4:c.259G>A variant in SLC6A8 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 87 (p.Gly87Arg). This variant is absent in population databases (PM2_Supporting) and has been described in the literature in an individual for whom biochemical testing could not be performed (PMID: 15154114). The computational predictor REVEL gives a score of 0.961 which is above the thresholds predicting a damaging (>0.75) impact on SLC6A8 function (PP3). When fibroblasts deficient for this SLC6A8 variant were grown in the presence of a physiological Cr concentration (25uM), the average creatine uptake was just above the detection limit, whereas in the control fibroblasts it was significantly higher (PMID: 17465020) (PS3_Supporting). There is a ClinVar entry for this variant (Variation ID:11700). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP, July 13, 2023)

Met criteria codes

• PP3: REVEL score for this variant is 0.961 (threshold of 0.75). So, PP3 is met.
• PM2_Supporting: Variant not seen in gnomAD
• PS3_Supporting: When SLC6A8-deficient fibroblasts were grown in the presence of a physiological Cr concentration (25uM), the average creatine uptake was just above the detection limit, whereas in the control fibroblasts it was significantly higher (PMID: 17465020).

Not Met criteria codes

• PS1: Not applicable for this variant
• PP4: This variant was reprted in a patient with X-linked disability; no biochemical or MRS analyses were performed (PMID: 15154114).