Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_005629.4(SLC6A8):c.395G>T (p.Gly132Val)

CA256014

11703 (ClinVar)

Gene: SLC6A8
Condition: creatine transporter deficiency
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: 3f675ac1-acab-4c6c-b20f-fc0ec17f3317
Approved on: 2024-04-11
Published on: 2024-06-12

HGVS expressions

NM_005629.4:c.395G>T
NM_005629.4(SLC6A8):c.395G>T (p.Gly132Val)
NC_000023.11:g.153691304G>T
CM000685.2:g.153691304G>T
NC_000023.10:g.152956759G>T
CM000685.1:g.152956759G>T
NC_000023.9:g.152609953G>T
NG_012016.1:g.8008G>T
NG_012016.2:g.8008G>T
ENST00000253122.10:c.395G>T
ENST00000675713.1:n.149G>T
ENST00000253122.9:c.395G>T
ENST00000430077.6:c.50G>T
ENST00000466243.1:n.187G>T
NM_001142805.1:c.395G>T
NM_001142806.1:c.50G>T
NM_005629.3:c.395G>T
NM_001142805.2:c.395G>T
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Likely Pathogenic

Met criteria codes 4
PP3 PS3_Supporting PM2_Supporting PP4_Strong
Not Met criteria codes 1
PS4

Evidence Links 2

Expert Panel

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cerebral Creatine Deficiency Syndromes VCEP
The NM_005629.4:c.395G>T variant in SLC6A8 is a missense variant that is predicted to result in the substitution of a glycine for a valine at amino acid 132 (p.Gly132Val). This variant has been previously reported one hemizygous male (PMID: 17101918, PMID: 23644449) who had elevated urinary creatine/creatinine and absent creatine peak on brain MRS (PMID: 17101918) (PP4_Strong). This variant was reported to result in <10% creatine transport activity when expressed in SLC6A8-deficient fibroblasts. A creatine concentration of 25uM was used, meeting the requirement for the assay to be carried out with less than or equal to 125uM creatine (PMID: 22281021, 23644449) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.916 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variation ID: 2290132). In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. ACMG/AMP SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4_Strong. (Classification approved by the ClinGen CCDS VCEP on April 11, 2024)
Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.916 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). No impact on splicing predicted by SpliceAI.
PS3_Supporting
This variant was reported to result in <10% creatine transport activity when expressed in SLC6A8-deficient fibroblasts. A creatine concentration of 25uM was used, meeting the requirement for the assay to be carried out with less than or equal to 125uM creatine (PMID: 22281021, 23644449) (PS3_Supporting).
This variant was reported to result in undetectable creatine transport activity in SLC6A8 deficient fibroblasts (PMID: 23644449) (PS3_Supporting). PubMed:23644449
This variant was reported to result in <10% creatine transport activity, with 25uM creatine, in SLC6A8 deficient fibroblasts (Figure 1, PMID: 23644449). PubMed:22281021
PM2_Supporting
The variant is absent in gnomAD v2.1.1. (PM2_Supporting).
PP4_Strong
This variant has been previously reported one hemizygous males (PMID: 17101918, PMID: 23644449) (PS4_Supporting) who had elevated urinary creatine/creatinine and absent creatine peak on brain MRS (PMID: 17101918) (PP4_Strong).
Not Met criteria codes
PS4
This variant has been previously reported one hemizygous males (PMID: 17101918, PMID: 23644449) (PS4_Supporting). Note that this case was counted for PP4 and thus not used for PS4 as per VCEP guidelines.
Curation History
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