ClinVar Miner

Submissions for variant NM_005629.4(SLC6A8):c.557G>A (p.Arg186His)

gnomAD frequency: 0.00001  dbSNP: rs372601430
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Total submissions: 3
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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 RCV000919928 SCV002600178 likely benign Creatine transporter deficiency 2022-06-06 reviewed by expert panel curation The NM_005629.4:c.557G>A variant in SLC6A8 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 186 (p.Arg186His). The highest population minor allele frequency in gnomAD is 0.00003675 in the European non-Finnish population which meets neither the PM2_Supporting (<0.00002) nor the BS1 (>0.0002) ClinGen CCDS VCEP allele frequency threshold. The variant is present in 2 or more hemizygotes in gnomAD v2.1.1 (BS2). Functional studies show that the variant results in 82% creatine transport of wild type when expressed in HeLa cells (PMID 25861866) (BS3_Supporting). The computational predictor REVEL gives a score of 0.102, evidence that does not predict a damaging effect on SLC6A8 function, and SpliceAI does not predict any impact of the variant on splicing (BP4). To our knowledge, this variant has not been reported in the literature in any patients with features of creatine transporter deficiency. There is a ClinVar entry for this variant (Variation ID: 516199). In summary, this variant meets the criteria to be classified as likely benign for creatine transporter deficiency. ACMG/AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2, BS3_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
GeneDx RCV000602976 SCV000728751 likely benign not specified 2018-01-29 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV000919928 SCV001065283 benign Creatine transporter deficiency 2023-08-27 criteria provided, single submitter clinical testing

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