ClinVar Miner

Submissions for variant NM_005629.4(SLC6A8):c.1216_1218TTC[2] (p.Phe408del) (rs80338740)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483506 SCV000568382 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing The c.1222_1224delTTC variant in the SLC6A8 gene has been reported previously in association with creatine transporter deficiency (Bizzi et al., 2002; Arias et al., 2007; Póo-Argüelles et al., 2006). The c.1222_1224delTTC variant causes an in-frame deletion of one amino acid, Phenylalanine 408, denoted p.Phe408del. Functional studies demonstrated the c.1222_1224delTTC variant did not generate any current in the presence of creatine, indicating that the electrogenic property and/or transport property was lost (Valayannopoulos et al., 2013). Additionally, the c.1222_1224delTTC variant was severely impaired in a creatine uptake assay (Valayannopoulos et al., 2013). This variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1222_1224delTTC as a pathogenic variant.
Invitae RCV000012464 SCV000640028 pathogenic Creatine transporter deficiency 2019-10-28 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 8 of the SLC6A8 mRNA (c.1222_1224delTTC). This leads to the deletion of 1 amino acid residue in the SLC6A8 protein (p.Phe408del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (rs80338740, ExAC no frequency). This variant is a common cause of X-linked creatine deficiency syndrome (PMID: 23644449). It has been observed in multiple individuals with laboratory findings that are highly specific for X-linked creatine deficiency syndrome (PMID: 16601898, 12210795, 21140503, 19706062) and it has been shown to arise de novo in an affected individual (PMID: 23660394). This variant is also known as c.1221_1223delTTC (p.Gly414del) in the literature. ClinVar contains an entry for this variant (Variation ID: 11698). Experimental studies have shown that this in-frame deletion reduces creatine uptake in both patient fibroblasts and a Xenopus oocyte model system (PMID: 22644605). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000483506 SCV001249764 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
OMIM RCV000012464 SCV000032698 pathogenic Creatine transporter deficiency 2002-08-01 no assertion criteria provided literature only
GeneReviews RCV000012464 SCV000041154 pathologic Creatine transporter deficiency 2011-08-18 no assertion criteria provided curation Converted during submission to Pathogenic.
GenomeConnect-Association for Creatine Deficiencies RCV000012464 SCV001169652 not provided Creatine transporter deficiency no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 01-00-1900 by GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant.

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