ClinVar Miner

Submissions for variant NM_005629.4(SLC6A8):c.338G>A (p.Gly113Asp)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen RCV003991436 SCV004809042 uncertain significance Creatine transporter deficiency 2024-03-28 reviewed by expert panel curation The NM_005629.4:c.338G>A variant in SLC6A8 is a missense variant that is predicted to result in the substitution of glycine by aspartate at amino acid 113 (p.Gly113Asp). This variant has been previously reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). This variant was reported to result in undetectable creatine transport activity, with 25uM creatine, when expressed in SLC6A8 deficient fibroblasts (PMID: 23644449) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.968 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is no ClinVar entry for this variant. In summary, while there is some suspicion for a pathogenic role, this variant currently meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024).

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