ClinVar Miner

Submissions for variant NM_005629.4(SLC6A8):c.1181C>A (p.Thr394Lys)

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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 RCV004597251 SCV005089693 uncertain significance Creatine transporter deficiency 2024-05-19 reviewed by expert panel curation The NM_005629.4:c.1181C>A variant in SLC6A8 is predicted to result in a missense substitution of threonine by lysine at amino acid 394 (p.Thr394Lys). A 5 year old Chinese male, hemizygous for the variant, has been reported with clinical features consistent with creatine tranporter deficiency, elevated creatine/creatinine ratio in urine (value not provided), and decreased creatine peak on brain MRS (PP4_Strong). A brother with similar clinical features, but no biochemical or MRS test results available, is also hemizygous for the variant, while the heterozygous mother is “physically normal” with normal creatine on MRS (insufficient evidence to apply PP1 based on the specifications of the ClinGen CCDS VCEP). The variant is absent in gnomAD v4.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.653 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function. SpliceAI predicts that the variant has no impact on splicing. In summary, this variant is of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on May 19, 2024)

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