Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000807506 | SCV002600176 | uncertain significance | Creatine transporter deficiency | 2022-06-06 | reviewed by expert panel | curation | The NM_005629.4:c.463G>A variant in SLC6A8 is a missense variant predicted to result in the substitution of glycerin by serine at amino acid 155 (p.Gly155Ser). In gnomAD v2.1.1, the highest population minor allele frequency is 0.00002 (2/80546 alleles) in the European non-Finnish population, which is equal to the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002), and lower and the allele frequency threshold for BS1. Therefore, no population data codes were applied. There are no hemizygotes in gnomAD v2.1.1.The computational predictor REVEL gives a score of 0.245 which is neither above the threshold predicting a damaging (>0.75) impact on SLC6A8 function, or below the threshold predicting a benign impact (<0.2). Therefore, neither code is met. To our knowledge, this variant has not been reported in the literature in any patient with creatine transporter deficiency. There is a ClinVar entry for this variant (Variation ID: 652028). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specifications version 1.1.0): No criteria were met. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). |
| Invitae | RCV000807506 | SCV000947562 | uncertain significance | Creatine transporter deficiency | 2018-08-14 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with serine at codon 155 of the SLC6A8 protein (p.Gly155Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with SLC6A8-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |