Submissions for variant NM_005629.4(SLC6A8):c.370T>C (p.Trp124Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV003991050	SCV004809043	uncertain significance	Creatine transporter deficiency	2024-03-28	reviewed by expert panel	curation	The NM_005629.4:c.370T>C variant in SLC6A8 is a missense variant that is predicted to result in the substitution of tryptophan by arginine at amino acid 124 (p.Trp124Arg). 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 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 0.866 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, 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. ACMG/AMP-specific 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).
Ambry Genetics	RCV002854159	SCV003624392	uncertain significance	Inborn genetic diseases	2022-06-13	criteria provided, single submitter	clinical testing	The c.370T>C (p.W124R) alteration is located in exon 2 (coding exon 2) of the SLC6A8 gene. This alteration results from a T to C substitution at nucleotide position 370, causing the tryptophan (W) at amino acid position 124 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional studies using transfected creatine deficient fibroblasts with the SLC6A8 ORF containing this variant showed that it did not restore creatine uptake to levels comparable to wildtype (Betsalel, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.