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]
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Variant: NM_001142805.2:c.1160C>T

CA415086358

Gene: SLC6A8
Condition: creatine transporter deficiency
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: 1879e63d-ce16-45ba-be85-54ff64e46827
Approved on: 2024-03-28
Published on: 2024-03-28

HGVS expressions

NM_001142805.2:c.1160C>T
NC_000023.11:g.153693953C>T
CM000685.2:g.153693953C>T
NC_000023.10:g.152959408C>T
CM000685.1:g.152959408C>T
NC_000023.9:g.152612602C>T
NG_012016.1:g.10657C>T
NG_012016.2:g.10657C>T
ENST00000253122.10:c.1190C>T
ENST00000253122.9:c.1190C>T
ENST00000413787.1:c.258-251C>T
ENST00000430077.6:c.845C>T
ENST00000442457.1:c.244C>T
ENST00000457723.1:c.174C>T
ENST00000467402.1:n.289C>T
ENST00000485324.1:n.1223C>T
NM_001142805.1:c.1160C>T
NM_001142806.1:c.845C>T
NM_005629.3:c.1190C>T
NM_005629.4:c.1190C>T

Likely Pathogenic

Met criteria codes 3
PM2_Supporting PP4_Strong PP3

Evidence Links 0

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.1190C>T variant in SLC6A8 is a missense variant that is predicted to lead to the substitution of a proline for a leucine at amino acid 397 (p.Pro397Leu). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine and deficient creatine uptake in cultured fibroblasts (PMID: 23644449) (PP4_Strong). This variant was reported to result in “residual” creatine transporter activity in SLC6A8 deficient fibroblasts without further specifications; thus, neither PS3 nor BS3 are met. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.896 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, PP3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024)
Met criteria codes
PM2_Supporting
The variant is absent in gnomAD v2.1.1. (PM2_Supporting).
PP4_Strong
This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine and deficient creatine uptake in cultured fibroblasts (PMID: 23644449) (PP4_Strong).
PP3
The computational predictor REVEL gives a score of 0.896 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3).
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