Submissions for variant NM_005629.4(SLC6A8):c.1016+2T>C

dbSNP: rs1557045066

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001803901	SCV003852680	pathogenic	Creatine transporter deficiency	2023-02-23	reviewed by expert panel	curation	The NM_005629.4:c.1016+2T>C variant occurs within the canonical splice donor of intron 6 of SLC6A8. It is predicted to cause skipping of biologically-relevant-exon 6/13, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two male patients have been reported who are hemizygous for the variant (presumed to be different cases). One of these patients has profound intellectual disability, seizures, and elevated urine creatine/creatinine ratio (PMID 16738945) (PP4). There was "clinical suspicion" for a CCDS for the other patient., but results of follow up biochemical testing or brain magnetic resonance spectrscopy are not available (PMID 23660394). There is a ClinVar entry for this variant (Variation ID: 520792). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Verions 1.1.0): PVS1, PP4, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on February 23, 2023).
Ambry Genetics	RCV000622581	SCV000741068	pathogenic	Inborn genetic diseases	2015-10-09	criteria provided, single submitter	clinical testing
Invitae	RCV001803901	SCV002300940	likely pathogenic	Creatine transporter deficiency	2021-05-09	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with SLC6A8-related conditions (PMID: 16738945, Invitae). ClinVar contains an entry for this variant (Variation ID: 520792). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 6 of the SLC6A8 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC6A8 are known to be pathogenic (PMID: 22281021).
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001803901	SCV002558932	pathogenic	Creatine transporter deficiency		criteria provided, single submitter	clinical testing
GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	RCV001803901	SCV002047664	not provided	Creatine transporter deficiency		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 07-13-2019 by lab or GTR ID 26957. GenomeConnect - Association for Creatine Deficiencies assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.